Tyrosyl derivatives and their use as P2X7 receptor modulators

ABSTRACT

The present invention relates to tyrosyl derivatives and their pharmaceutically acceptable salts; compositions thereof and methods of preparing the compounds are also described. The compounds are useful in the treatment of diseases in mammals that are mediated by the action of the P2X 7  receptor.

RELATED APPLICATION

[0001] This Application claims the benefit of Provisional ApplicationNo. 60/342,977 filed Dec. 21, 2001.

BACKGROUND OF THE INVENTION

[0002] The present invention relates generally to the field ofpurinergic P2 receptors. More particularly, the present inventionrelates to novel purinergic P2X receptor compounds and productionthereof. In further detail, the present invention relates to compounds,their intermediates, and enantiomers of both which have P2X receptorsubtype 7 (P2X₇) binding inhibition activity, and are useful forpreventing and/or treating diseases associated with adenosine5′-triphosphate or other natural or synthetic nucleotides.

[0003] P2 receptors have been generally categorized as eithermetabotropic nucleotide receptors or inotropic receptors forextracellular nucleotides. Metabotropic nucleotide receptors (usuallydesignated P2Y or P2Y_(n), where “n” is a subscript integer indicatingsubtype) are believed to differ from inotropic receptors (usuallydesignated P2X or P2X_(n)) in that they are based on a differentfundamental means of transmembrane signal transduction: P2Y receptorsoperate through a G protein-coupled system, while P2X receptors areligand-gated ion channels. The ligand for these P2X receptors is ATP,and/or other natural nucleotides, for example, ADP, UTP, UDP, and/orsynthetic nucleotides, for example 2-methylthioATP.

[0004] A therapeutic role for P2 receptors has been suggested, forexample, for cystic fibrosis (Boucher et al. (1995) in: Belardinelli etal. (eds) Adenosine and Adenine Nucleotides: From Molecular Biology toIntegrative Physiology (Kluwer Acad., Norwell Mass.) pp 525-532),diabetes (Loubatieres-Mariani et al. (1995) in: Belardinelli et al.(eds), supra, pp 337-345), immune and inflammatory diseases (Di Virgilioet al. (1995) in: Belardinelli et al. (eds), supra, pp 329-335), cancer(Rapaport (1993) Drug Dev. Res. 28:428-431), constipation and diarrhea(Milner et al. (1994) in: Kamm et al. (eds.) Constipation and RelatedDisorders: Pathophysiology and Management in Adults and Children(Wrightson Biomedical, Bristol) pp 41-49), behavioral disorders such asepilepsy, depression and aging-associated degenerative diseases(Williams (1993) Drug. Dev. Res. 28:438-444), contraception andsterility (Foresta et al. (1992) J. Biol. Chem. 257:19443-19447), andwound healing (Wang et al. (1990) Biochim. Biophys. Res. Commun.166:251-258).

[0005] At least seven P2X receptors, and the cDNA sequences encodingthem, have been identified to date. P2X₁ cDNA was cloned from the smoothmuscle of the rat vas deferens (Valera et al (1994) Nature 371:516-519)and P2X.₂ cDNA was cloned from PC12 cells (Brake et al. (1994) Nature371:519-523). Five other P2X receptors have been found in cDNA librariesby virtue of their sequence similarity to P2X₁ and P2X₂ (P2X₃: Lewis etal. (1995) Nature 377:432-435, Chen et al. (1995) Nature 377:428-431;P2X₄: Buell et al. (1996) EMBO J. 15:55-62, Seguela et al. (1996) J.Neurosci. 16:448-455, Bo et al. (1995) FEBS Lett. 375:129-133, Soto etal. (1996) Proc. Natl. Acad. Sci. USA 93:3684-3688, Wang et al. (1996)Biochem. Biophys. Res. Commun. 220:196-202; P2X₅: Collo et al. (1996) J.Neurosci. 16:2495-2507, Garcia-Guzman et al. (1996) FEBS Lett.388:123-127; P2X₆: Collo et al. (1996), supra, Soto et al. (1996)Biochem. Biophys. Res. Commun. 223:456-460; P2X₇: Surprenant et al.(1996) Science 272:735-738). For a comparison of the amino acidsequences of rat P2X receptors see Buell et al. (1996) Eur. J. Neurosci.8:2221-2228.

[0006] Native P2X receptors form rapidly activated, nonselectivecationic channels that are activated by ATP. Rat P2X₁ and rat P2X₂ haveequal permeability to Na⁺ and K⁺ but significantly less to Cs⁺. Thechannels formed by the P2X receptors generally have high Ca²⁺permeability. The cloned rat P2X₁, P2X₂ and P2X₄ receptors exhibit thesame permeability for Ca²⁺ observed with native receptors. However, themechanism by which P2X receptors form an ionic pore or bind ATP is notknown.

[0007] A variety of tissues and cell types, including epithelial,immune, muscle and neuronal, express at least one form of P2X receptor.The widespread distribution of P2X₄ receptors in the rat central nervoussystem suggests a role for P2X₄-mediated events in the central nervoussystem. However, study of the role of individual P2X receptors ishampered by the lack of receptor subtype-specific agonists andantagonists. For example, one agonist useful for studying ATP-gatedchannels is α,β methylene ATP (meATP). However, the P2X receptorsdisplay differential sensitivity to the agonist with P2X, and P2X₂ beingmeATP-sensitive and insensitive, respectively. Furthermore, binding ofmeATP to P2X receptors does not always result in channel opening. Thepredominant forms of P2X receptors in the rat brain, P2X₄ and P2X₆receptors, cannot be blocked by suramin or PPADS. These two forms of theP2X receptor are also not activated by meATP and are, thus, intractableto study with currently available pharmacological tools.

[0008] The functional properties of the P2X₁₋₆ receptors arefundamentally similar to those of the other two ionotropic receptors,the nicotinic and excitatory amino acid receptors, and are thenrelatively impermeable to cations that are more than about 200 D.

[0009] One of the most interesting members of the ionotropic P2X familyis the P2X₇ receptor. Di Virgilio, F., et. al. (1998) Cell Death andDifferentiation 5:191; Di Virgilio, F., et. al. (1995) Immunology Today16:524. The P2X₇ ionic channel differs strikingly from these channelsand it is formed by the aggregation of an unknown number of subunitseach 595 aminoacids (AA) long (200 AA longer than the other six P2Xreceptor), and upon stimulation by high concentrations of extracellularATP generates a nonselective membrane pore of variable size (3-5 nm) andpermeable to hydrophilic molecules with molecular weight up to 900Dalton. Suprenant, A., et. al. (1996) Science 272:735.

[0010] Selective activation of the P2X₇ receptor inmycobacterial-infected cells may provide a new therapy for tuberculosis,as well as an effective anticancer agent for many tumors that are richin P2X₇ receptor. This receptor is mainly, if not exclusively, expressedby mononuclear phagocytes, where it mediates cytotoxic responses,cytokine release and cell fusion. Di Virgilio, F., et. al., (1998) DrugDev. Res.45:207; Falzoni, S., et. al. (1995) J. Clin. Invest. 95:1207.Activation of the P2X₇ receptor in macrophages and microglial cellscauses a large and rapid release of mature interleukin-1β in response tolipopolysaccaride (LPS) stimulation.

[0011] IL-1β is of prime importance in the induction of the immuneresponses, including facilitating response to antigens, synthesis ofprostaglandins, proliferation of fibroblasts, blood neutrophils, andinducing the synthesis of other cytokines. Due to likely involvement inimmunomodulation and in the inflammatory reaction, it would be of themost importance to develop selective P2X₇ antagonists.

[0012] Human macrophages have proven very useful for the evaluation ofP2X₇ agonists and antagonists. Compound KN62(1-N,0-(bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl)-4-phenylpiperazine)is one of the most potent antagonists for the P2X₇ receptor withcomplete inhibition at the concentration of 500 nM. Gargett, C. E. et.al. (1997) B. J. Pharmacol. 120:1483. KN62 is a specific cell-permeableinhibitor of the autophosphorylation of Ca²⁺/calmodulin-dependentprotein kinase II (CaMK II) and may be useful as a pharmacological toolfor evaluating the role of CaMK II. Hidaka, H. et. al. (1992) Ann. Rev.Pharmacol. Toxicol., 32:377 (1992).

[0013] CaMK II is one of the important kinases whose response seems tobe mediated by calmodulin, and that is proposed as a regulator for thesynthesis and vescicular release of neurotransmitters. The same compoundKN62 significantly inhibited both stimulated catecholamine release andsecretory function via the direct blockade of activated Ca²⁺ influx.Maurer, J. A. et. al. (1996) J. Neurochem 66:105. KN62, at non-cytotoxicconcentration (2 μM), enhanced etoposide (VP-16) cytotoxicity inAdriamycin-resistant cells (HL-60) and this is due to enhancement (from2-to 4-fold) of VP-16 induced topoisomerase II-mediated DNA cleavablecomplex formation. Kawamura, K., et. al. (1996) Biochem Pharmacol.12:1903. The DNA damage induced by VP-16 in the presence of KN62resulted in the rapid introduction of apoptosis and depletion of cell in“S phase” of the cell cycle.

[0014] Thus, what is needed is specific agonists and antagonists for theP2X₇ receptor subtype and, in particular, agents that will be effectivein vivo, useful in the treatment of patients, as well as methods foridentifying the P2X₇ receptor-specific agonist and antagonist compounds.

BRIEF SUMMARY OF THE INVENTION

[0015] The present invention comprises various novel compounds, theirintermediates, their pharmaceutically acceptable salts, methods oftreatment of medical conditions and methods for identifying receptors inmammals.

[0016] It is an object of the present invention to provide novelcompounds, their intermediates, and their pharmaceutically acceptablesalts.

[0017] It is another object of the invention to provide ligandsselective for the P2X₇ receptor that have a broader therapeutic indexthan those currently available.

[0018] It is a further object of the invention to provide P2X₇ receptorantagonists.

[0019] It is a further object to of the invention to provide compoundshaving activity as anti-inflammatories.

[0020] It is yet another object of the invention to provide compoundshaving activity that enhance endocrine function and hormonal modulation.

[0021] It is a further object of the invention to provide compoundsuseful in modulating or inhibiting the immune response.

[0022] It is another object of the invention to provide compounds havingactivity which will induce apoptosis either when administered singly orin combination with other agents.

[0023] Additional objects and advantages of the present invention willbe apparent in the following detailed description read in conjunctionwith the accompanying table, and figures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024]FIG. 1 illustrates the general synthesis procedure for compoundsof formula I.

[0025]FIG. 2 illustrates the general synthesis procedure for compoundsof formula II.

[0026]FIG. 3 illustrates the general synthesis procedure for compoundsof formula III.

[0027]FIG. 4 illustrates the general synthesis procedure for compoundsof formula IV.

[0028] Table 1 illustrates the IC50 values for compounds towardinhibiting calcium influx in human monocytes in the presence of 1 mMATP.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The inventors have synthesized and evaluated the antagonistactivities of a series of P2X₇ receptor ligands.

[0030] The general structure of the compounds of the present inventionare illustrated in Formulas I, II, III, and IV:

[0031] wherein R₁ and R₂ are independently hydrogen, C1-C4 alkyl, C1-C4alkoxy,

[0032] halogen, cyano, nitro, amino, or C1-C4 acyl;

[0033] R₃, R₄, R₅, R₆, R₇, and R₈ are independently CH or nitrogen;

[0034] R₉ is independently hydrogen or methyl;

[0035] R₁₀ is independently carbonyl or (CH₂)_(n); where n is 0, 1, 2,3, or 4;

[0036] R₁₁ is independently nitrogen or CH;

[0037] R₁₂ is independently nitrogen or CH;

[0038] X₁ and X₂ are independently halogen or tritium; and

[0039] X₃ is N or CH.

[0040] wherein R₁ is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 acyl,halogen, cyano, nitro, amino, alkylamino, or dialkylamino; X₁ and X₂ areindependently hydrogen, deuterium, tritium, or halogen.; R₉ is methyl orhydrogen.

[0041] wherein R₁ and R₂ are independently hydrogen, C1-C4 alkyl, C1-C4alkoxy, C1-C4 acyl, halogen, cyano, nitro, amino, alkylamino ordialkylamino; R₉ is hydrogen or methyl; X₁ and X₂ are independentlyhydrogen, deuterium, tritium, or halogen; and X₃ is independentlynitrogen or CH.

[0042] wherein R₁ and R₂ are independently hydrogen, C1-C4 alkyl, C1-C4alkoxy, halogen, cyano, nitro, or amino;

[0043] R₃, R₄, R₅, R₆, R₇, and R₈ are independently CH or nitrogen;

[0044] n is 0, 1, 2, 3, 4; and

[0045] with the proviso that when n is 0 either R₁ or R₂ is nothydrogen.

[0046]FIG. 1 illustrates the synthetic process for the formation of thecompounds of Formula I and their intermediates. In summary, thesecompounds are prepared from an N-Boc-protected-tyrosine derivative.These amino-protected precursors are converted to the activated1-hydroxy-1,2,3-benzotriazole (HOBt) esters with HOBt and EDC andcoupled with the appropriate substituted-aryl, aralkyl, heteroaryl, orheteroaralkylpiperazines or piperidines to afford the requisite amidesin good yields. The phenolic anion of the tyrosyl-moiety compounds(generated in situ with sodium hydride) is converted to thecorresponding heteroarylsulfonyl ester by treatment with adichloromethane (CH₂Cl₂) solution of the requisite heteroarylsulfonylchloride. Removal of the amine protecting tert-butyloxycarbonyl (Boc)group is conveniently effected with trifluoroacetic acid (TFA) in aCH₂Cl₂ solution to provide the corresponding free amine. Thisintermediate is then coupled with an excess of the desiredheteroarylsulfonyl chloride to provide the desired sulphonamides inacceptable yields. Reagents and conditions referred to in FIG. 1 are: a.N-substituted aryl, aralkyl, heteroaryl, or heteroaralkyl piperazine orpiperidine, HOBt, EDC, DMF. b. Sodium hydride, heteroarylsulfonylchloride, CH₂Cl₂. c. Trifluoroacetic acid, CH₂Cl₂. d. Triethylamine,heteroarylsulfonyl chloride, CH₂Cl₂.

[0047]FIG. 2 illustrates the synthetic process for the formation of thecompounds of Formula II and their intermediates. In summary, thesecompounds are prepared from an N-Boc-protected-tyrosine derivative.These amino-protected precursors are converted to the activated1-hydroxy-1,2,3-benzotriazole (HOBt) esters with HOBt and EDC andcoupled with the appropriate 3,4-dihydro-1H-pyrazino[1,2-a]indole toafford the requisite amides in good yields. The phenolic anion of thetyrosyl-moiety compounds (generated in situ with sodium hydride) isconverted to the corresponding isoquinolinesulfonyl ester by treatmentwith a dichloromethane (CH₂Cl₂) solution of the requisiteisoquinolinesulfonyl chloride. Removal of the amine protectingtert-butyloxycarbonyl (Boc) group is conveniently effected withtrifluoroacetic acid (TFA) in a CH₂Cl₂ solution to provide thecorresponding free amine. This intermediate is then coupled with anexcess of the desired isoquinolinesulfonyl chloride to provide thedesired sulphonamides in acceptable yields. Reagents and conditions forthe reactions referred to in FIG. 2 are: a. Substituted1,2,3,4-tetrahydropyrazino[1,2-a]indole, HOBt, EDC, DMF. b. Sodiumhydride, isoquinoline-5-sulfonyl chloride, CH2Cl2. c. Trifluoroaceticacid, CH2Cl2. d. Triethylamine, isoquinoline-5-sulfonyl chloride,CH2Cl2.

[0048]FIG. 3 illustrates the synthetic scheme followed in thepreparation of compounds of Formula III and their intermediates. Thesecompounds are prepared from an appropriately substitutedN-Boc-protected-tyrosine. These precursors are converted to theactivated 1-hydroxy-1,2,3-benzotriazole (HOBt) esters with HOBt and EDCand coupled with the desired substituted-N-arylpiperazines to providethe requisite amides in good yields. The phenolic anion of thetyrosyl-moiety compounds (generated in situ with sodium hydride) isconverted to the corresponding 3-pyridinesulfonyl ester by treatmentwith a dichloromethane (CH₂Cl₂) solution of the requisite3-pyridinesulfonyl chloride. Removal of the amine protectingtert-butyloxycarbonyl (Boc) group is conveniently effected withtrifluoroacetic acid (TFA) in a CH₂Cl₂ solution to provide thecorresponding free amine. This intermediate is then coupled with aexcess of 3-pyridinesulfonyl chloride to provide the target products inacceptable yields. Reagents and conditions for the reactions referred toin FIG. 3: a. Substituted arylpiperazine or arylpiperidine, HOBt, EDC,DMF. b. Sodium hydride, pyridine-3-sulfonyl chloride, CH₂Cl₂. c.Trifluoroacetic acid, CH₂Cl₂. d. Triethylamine, pyridine-3-sulfonylchloride, CH₂Cl₂.

[0049]FIG. 4 illustrates the synthetic process for the formation of thecompounds of Formula IV and their intermediates. In summary, thesecompounds are prepared from an N-Boc-protected-tyrosine derivative.These amino-protected precursors are converted to the activated1-hydroxy-1,2,3-benzotriazole (HOBt) esters with HOBt and EDC andcoupled with the appropriate substituted-N-arylpiperazines orsubstituted-N-aralkylpiperazines, affording the requisite amides in goodyields. The phenolic anion of the tyrosyl-moiety compounds (generated insitu with sodium hydride) is converted to the correspondingheteroarylsulfonyl ester by treatment with a dichloromethane (CH₂Cl₂)solution of the requisite heteroarylsulfonyl chloride. Removal of theamine protecting tert-butyloxycarbonyl (Boc) group is convenientlyeffected with trifluoroacetic acid (TFA) in a CH2Cl2 solution to providethe corresponding free amine. This intermediate is then coupled with aexcess of the desired heteroarylsulfonyl chloride to provide the desiredsulphonamides in acceptable yields. Reagents and conditions for thereactions referred to in FIG. 4 are: a. Substituted aryl oraralkylpiperazine, HOBt, EDC, DMF. b. Sodium hydride, heteroarylsulfonylchloride, CH2Cl2. c. Trifluoroacetic acid, CH2Cl2. d. Triethylamine,heteroarylsulfonyl chloride, CH2Cl2.

[0050] Where the plural form is used for compounds, and salts, this istaken to mean also a single compound or salt. Any asymmetric carbonatoms may be present in the (R)-, (S)- or (R, S) configuration.Substituents at a double bond or a ring may be present in cis-(Z) ortrans (E) form. The compounds may thus be present as mixtures of isomersor as pure isomers. In cases wherein compounds may exist in tautomericforms, each tautomeric form is contemplated as being included withinthis invention whether existing in equilibrium or predominantly in oneform.

[0051] Certain of the compounds of the present invention aresufficiently basic, (e.g., amino derivatives) or acidic (e.g.,carboxylic acid derivatives) to form salts. Pharmaceutically acceptablesalts of the compounds of formulas I are within the scope of the presentinvention. As will be understood by those skilled in the art,pharmaceutically acceptable salts include, but are not limited, to saltswith inorganic acids such as hydrochloride, sulfate, phosphate,hydrobromide, and nitrate or salts with an organic acid such as malate,maleate, fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, palmoate, salicylate, andstearate. Other acids such as oxalic, while not in themselvespharmaceutically acceptable, may be useful as intermediates in obtainingthe compounds of the invention and their pharmaceutical salts.

[0052] Compounds with particularly significant IC50 values would beuseful for the identification and labeling of P2X receptors in mammals.This would make them useful as diagnostic agents for P2X receptors.

[0053] The compounds and their intermediates are formed in the followingsteps:

[0054] Step a. General Procedure for the Synthesis of Compounds B_(i).

[0055] General procedure (A) for the synthesis of compounds B_(i) ofFIG. 1. To a solution of A_(i) (1 mmole) in dry DMF (5 mL) cooled at 0°C. was added EDC (211 mg, 1.1 mmol, 1.1 equiv.), HOBt (1.1 mmol) and thesuitable N-substituted piperazine (1.1 mmol). This mixture was stirredfor 18 h and then concentrated in vacuo. The residue was dissolved inEtOAc (10 mL), washed with water (5 mL) and then with brine (5 mL). Theorganic layer was dried (Na₂SO₄) and concentrated in vacuo. The residuepurified by column chromatography furnished the derivatives B_(i).

[0056]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(benzyl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield >95%); m.p.=104-106° C., [α]=−63.7, c=0.91% in CHCl₃.1H-NMR (CDCl₃) δ: 1.36 (s, 9H), 2.28 (m, 4H), 2.79 (s, 3H), 2.83 (s,2H), 2.89 (dd, J=16.7 and 7.3 Hz, 2H), 3.49 (m, 4H), 5.21 (t, J=7.3 Hz,1H), 5.85 (s, 1H), 6.72 (d, J=8.3 Hz, 2H), 7.05 (d, J=8.3 Hz, 2H), 7.20(m, 5H).

[0057]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(phenethyl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield 46%); m.p.=1147-150° C., [α]=−46.8, c=1.5% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.37 (s, 9H), 2.38 (m, 4H), 2.58 (m, 2H), 2.75 (m,2H), 2.81 (s, 3H), 2.89 (dd, J=14.1 and 8.3 Hz, 2H), 3.49 (m, 4H), 5.21(t, J=8.3 Hz, 1H), 5.49 (s, 1H), 6.70 (d, J=8.3 Hz, 2H), 7.00 (d, J=8.3Hz, 2H), 7.23 (m, 5H).

[0058]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorophenyl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield 94%); m.p.=67-69° C., [α]=−85.4, c=1.29% in CHCl₃. 1H-NMR (CDCl₃) δ: 1.34 (s, 9H), 2.78 (s, 3H), 2.89 (dd, J=16.7 and 7.3Hz, 2H), 3.07 (m, 4H), 3.50 (m, 4H), 5.21 (t, J=7.3 Hz, 1H), 5.85 (s,1H), 6.86 (m, 8H).

[0059]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-chlorophenyl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield 78%); m.p.=73-75° C., [α]=−77, c=0.76% in CHCl₃.1H-NMR (CDCl₃) δ: 1.39 (s, 9H), 1.56 (m, 2H), 2.89 (s, 3H), 2.95 (m,4H), 3.54 (m, 4H), 5.25 (t, J=7.2 Hz, 1H), 6.78 (m, 3H), 7.02 (d, J=8.4Hz, 1H), 7.09 (d, J=8.2 Hz, 2H), 7.22 (m, 2H), 9.46 (s, 1H).

[0060]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-iodophenyl)-piperazine.Following the general procedure (A), this product was obtained as ayellow solid (yield 92%); m.p.=73-75° C., [α]=-65.4, c=1.02% in CHCl₃.1H-NMR (CDCl₃) δ: 1.38 (s, 9H), 2.82 (s, 3H), 2.93 (dd, J=14.6 and 7.2Hz, 2H), 3.12 (m, 4H), 3.51 (m, 4H), 5.24 (t, J=7.2 Hz, 1H), 5.82 (s,1H), 6.61 (d, J=8.8 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz,2H), 7.52 (d, J=8.8 Hz, 2H).

[0061]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(p-tolyl)-piperazine.Following the general procedure (A), this product was obtained as a foamoil (yield 93%); [α]=−83.3, c=1.34% in CHCl₃. 1H-NMR (CDCl₃) 6:1.38 (s,9H), 2.27 (s, 3H), 2.81 (s, 3H), 2.86 (dd, J=14 and 7.6 Hz, 2H), 3.42(m, 4H), 3.54 (m, 4H), 5.26 (t, J=7 Hz, 1H), 6.80 (m, 4H), 7.06 (m, 4H),9.5 (s, 1H).

[0062]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-methoxyphenyl)-piperazine.Following the general procedure (A), this product was obtained as a foamyellow solid (yield 89%); [α]=-63.3, c=1.1% in CHCl₃. 1H-NMR (CDCl₃) δ:1.38 (s, 9H), 2.82 (s, 3H), 2.87 (m, 6H), 3.52 (m, 4H), 3.77 (s, 3H),5.26 (t, J=7.2 Hz, 1H), 6.71 (d, J=8.4 Hz, 2H), 6.84 (m, 2H), 7.02 (d,J=8.6 Hz, 2H), 7.10 (d, J=8.6 Hz, 2H), 9.46 (s, 1H).

[0063]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(4-nitrophenyl)-piperazine.Following the general procedure (A), this product was obtained as ayellow solid (yield 88%); m.p.=211-213° C., [α]=−66.7, c=1.02% in CHCl₃.1H-NMR (CDCl₃) δ: 1.39 (s, 9H), 2.74 (dd, J=14 and 7.6 Hz, 2H), 2.84 (s,3H), 3.34 (m, 4H), 3.56 (m, 4H), 5.25 (t, J=7.2 Hz, 1H), 6.71 (d, J=3.4Hz, 2H), 6.76 (d, J=3.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 8.12 (d, J=9.2Hz, 2H). 9.5 (s, 1H).

[0064]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-cyanophenyl)-piperazine.Following the general procedure (A), this product was obtained as a oil(yield 76%); [α]=−49.7, c=1.47% in CHCl₃. 1H-NMR (CDCl₃) δ: 1.39 (s,9H), 1.56 (m, 2H), 2.84 (s, 3H), 3.10 (m, 4H), 3.52 (m, 4H), 5.31 (t,J=7.2 Hz, 1H), 6.73 (d, J=8.6 Hz, 2H), 6.79 (d, J=9.2 Hz, 2H), 7.11 (d,J=8.2 Hz, 2H), 7.48 (d, J=8.8 Hz, 2H), 9.46 (s, 1H).

[0065]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-acetylphenyl)-piperazine.Following the general procedure (A), this product was obtained as ayellow solid (yield); m.p.=° C., [α]=0.1H-NMR (CDCl₃) δ: 1.34 (s, 9H),2.53 (s, 3H), 2.84 (s, 3H), 2.93 (dd, J=14.8 and 7.3 Hz, 2H), 3.42 (m,4H), 3.54 (m, 4H), 5.26 (t, J=7.3 Hz, 1H), 5.91 (s, 1H), 6.77 (m, J=8Hz, 4H), 7.10 (d, J=8 Hz, 2H), 7.87 (d, J=8 Hz, 2H).

[0066]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzyl)-piperazine.Following the general procedure (A), this product was obtained as abrown oil (yield 78%); [α]=−62.2, c=0.49% in CHCl₃. 1H-NMR (CDCl₃) δ:1.37 (s, 9H), 2.37 (m, 4H), 2.84 (s, 5H), 2.94 (m, 1H), 3.11 (m, 1H),3.53 (m, 4H), 4.57 (m, 1H), 5.16 (t, J=7.3 Hz, 1H), 6.78 (d, J=8.1 Hz,2H), 7.00 (m, J=8.4 Hz, 4H), 7.21 (d, J=8.2 Hz, 2H).

[0067]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzoyl)-piperazine.Following the general procedure (A), this product was obtained as awhite oil (yield 97%); [α]=−10.6, c=1.18% in CH₂Cl₂. 1H-NMR (CDCl₃) δ:1.38 (s, 9H), 2.85 (s, 3H), 3.00 (m, 2H), 3.50 (m, 8H), 4.57 (m, 1H),5.16 (m, 1H), 6.73 (d, J=8.3 Hz, 2H), 7.08 (m, 4H), 7.38 (d, J=8.2 Hz,2H).

[0068]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-nitrobenzyl)-piperazine.Following the general procedure (A), this product was obtained as abrown oil (yield 78%); [α]=−30, c=0.46% in CHCl₃. 1H-NMR (CDCl₃) δ: 1.35(s, 9H), 2.35 (m, 4H), 2.82 (s, 2H), 2.89 (m, 2H), 2.96 (s, 3H), 3.51(m, 4H), 4.88 (m, 1H), 5.19 (m, 1H), 6.75 (d, J=8.5 Hz, 2H), 7.05 (d,J=8.5 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H), 8.14 (d, J=8.3 Hz, 2H).

[0069]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-fluorophenyl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield 78%); m.p.=73-75° C., [α]=−77, c=0.76% in CHCl₃.1H-NMR (CDCl₃) δ: 1.38 (s, 9H), 2.84 (s, 3H), 2.94 (m, 4H), 3.11 (dd,J=13.8 and 7.6 Hz, 2H), 3.58 (m, 4H), 5.26 (t, J=7.2 Hz, 1H), 6.76 (m,3H), 7.01 (m, 5H), 9.46 (s, 1H).

[0070]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-chlorophenyl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield >95%); m.p.=70-72° C., [α]=−70.3, c=1.15% in CHCl₃.1H-NMR (CDCl₃) δ: 1.38 (s, 9H), 2.84 (s, 3H), 2.91 (m, 6H), 3.71 (m,4H), 5.25 (t, J=7.2 Hz, 1H), 5.82 (s, 1H), 6.74 (m, 2H), 7.04 (m, 5H),7.34 (d, J=9.2, Hz 1H).

[0071]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield 95%); m.p.=80-82° C., [α]=−66.7, c=1.9% in CHCl₃.1H-NMR (CDCl₃) δ: 1.38 (s, 9H), 2.28 (s, 3H), 2.74 (m, 6H), 2.86 (s,3H), 3.65 (m, 4H), 5.26 (t, J=7.2 Hz, 1H), 6.01 (s, 1H), 6.74 (m, 2H),7.10 (m, 6H).

[0072]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-methoxyphenyl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield >95%); m.p.=153-155° C., [α]=−126.9, c=0.93% inCHCl₃. 1H-NMR (CDCl₃) δ: 1.38 (s, 9H), 2.83 (s, 3H), 2.93 (m, 6H), 3.64(m, 4H), 3.86 (s, 3H), 5.27 (t, J=7.2 Hz, 1H), 5.82 (s, 1H), 6.72 (m,3H), 6.89 (m, 2H), 7.06 (m, 3H).

[0073]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(3-chlorophenyl)-piperazine.Following the general procedure (A), this product was obtained as ayellow solid (yield 93%); m.p.=60-62° C., [α]=-72, c=0.88% in CHCl₃.1H-NMR (CDCl₃) δ: 1.36 (s, 9H), 2.83 (s, 3H), 2.99 (m, 6H), 3.52 (m,4H), 5.26 (t, J=7.2 Hz, 1H), 6.76 (m, 4H), 7.12 (m, 4H), 9.46 (s, 1H).

[0074]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3-trifluoromethyl-phenyl)-piperazine(27). Following the general procedure (A), this product was obtained asa yellow solid (yield 78%); m.p.=102-104° C., [α]=−63.4, c=0.8% inCHCl₃. 1H-NMR (CDCl₃) δ: 1.39 (s, 9H), 2.83 (s, 3H), 3.04 (m, 6H), 3.56(m, 4H), 5.25 (t, J=7.2 Hz, 1H), 5.82 (s, 1H), 6.73 (d, J=8.3 Hz, 2H),7.02 (m, 3H), 7.10 (d, J=8.3 Hz, 2H), 7.35 (m, 1H).

[0075]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(2,3-dimethylphenyl)-piperazine.Following the general procedure (A), this product was obtained as a oil(yield 91%); [α]=−20.3, c=0.7% in CH₂Cl₂. 1H-NMR (CDCl₃) δ: 1.44 (s,9H), 2.18 (s, 3H), 2.26 (s, 3H), 2.85 (s, 3H), 2.93 (m, 6H), 3.65 (m,4H), 5.25 (t, J=7.2 Hz, 1H), 5.82 (s, 1H), 6.76 (m, 3H), 6.94 (m, 1H),7.06 (m, 3H).

[0076]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3,4-dichlorophenyl)-piperazineFollowing the general procedure (A), this product was obtained as awhite solid (yield 85%); m.p.=77-78° C., [α]=−71.4, c=0.42% in CHCl₃.1H-NMR (CDCl₃) δ: 1.39 (s, 9H), 2.84 (s, 3H), 2.99 (m, 6H), 3.56 (m,4H), 5.25 (t, J=7.2 Hz, 1H), 6.75 (m, 2H), 6.88 (m, 1H), 7.08 (m, 2H),7.26 (m, 2H), 9.46 (s, 1H).

[0077]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(pyridin-2-yl)-piperazine.Following the general procedure (A), this product was obtained as awhite oil (yield 89%); [α]=−57.1, c=0.7% in CH₂Cl₂. 1H-NMR (CDCl₃) δ:1.39 (s, 9H), 2.83 (s, 3H), 2.97 (m, J=7.6 Hz, 1H), 3.50 (m, 9H), 4.95(m, 1H), 5.26 (t, J=7.5 Hz, 1H), 6.66 (m, J=8.6 Hz, 4H), 7.05 (m, J=8.3Hz, 2H), 7.49 (m, 1H), 8.18 (m, 1H).

[0078]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(pyrimidin-2-yl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield 91%); m.p.=109-111° C., [α]=−54.5, c=0.27% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.38 (s, 9H), 2.83 (s, 3H), 3.02 (m, 2H), 3.53 (m,5H), 3.88 (m, 3H), 4.92 (m, 1H), 5.26 (t, J=7.5 Hz, 1H), 6.53 (m, 1H),6.72 (m, 2H), 7.09 (m, J=8.3 Hz, 2H), 8.32 (m, 1H).

[0079]1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(benzyl)-piperidine.Following the general procedure (A), this product was obtained as awhite solid (yield >95%); m.p.=70-72° C., [α]=−61.7, c=0.46% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.39 (s, 9H), 1.62 (m, 5H), 2.50 (m, 3H), 2.86 (m,J=12.6 and 6.8 Hz, 6H), 3.95 (m, 1H), 4.58 (m, 1H), 5.21 (t, J=6.8 Hz,1H), 5.85 (s, 1H), 6.72 (m, J=7.5 Hz, 2H), 7.10 (m, 4H), 7.25 (m, 3H).

[0080]1-[(S)-N-tert-butyloxycarbonyl-tyrosyl]-4-(4-fluorophenyl)-piperazine.Following the general procedure (A), this product was obtained as a foamyellow oil (yield 87%); [α]=+7.0, c=0.43% in CH₂Cl₂. 1H-NMR (CDCl₃) δ:1.43 (s, 9H), 2.93 (m, 6H), 3.57 (m, 4H), 4.82 (t, J=8.6 Hz, 1H),5.45(s, 1H), 6.75 (m, 4H), 6.93 (d, J=8.4 Hz, 2H), 7.04 (d, J=8.4 Hz,2H).

[0081] 1-[(S)-N-tert-butyloxycarbonyl-tyrosyl]-4-(o-tolyl)-piperazine.Following the general procedure (A), this product was obtained as awhite solid (yield 94%); m.p.=80-82° C., [α]=+14.9, c=1.03% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.43 (s, 9H), 2.26 (s, 3H), 2.31 (m, 1H), 2.69 (m,3H), 2.92 (d, J=6.9 Hz, 2H), 3.29 (m, 1H), 3.46 (m, 1H), 3.69 (m, 2H),4.85 (dd, J=15.7 and 7.3 Hz, 1H), 5.47 (d, J=8.6 Hz, 1H), 6.20 (s, 1H),6.74 (d, J=8.4 Hz, 2H), 6.86 (d, J=7.7 Hz, 1H), 7.03 (m, J=8.4 Hz, 3H),7.15 (t, J=7.4 Hz, 2H).

[0082][2-(3,4-Dihydro-1H-pyrazino[1,2-a]indol-2-yl)-1-(4-hydroxy-benzyl)-2-oxo-ethyl]-carbamicacid tert-butyl ester. Following the general procedure (A) this productwas obtained. m.p. 85-87° C.; [α]=−4.1, c=0.9% in CHCl₃; 1H-NMR (CDCl₃):d 1.44 (s, 9H), 2.90 (t, J=4 Hz, 2H), 3.52 (m, 1H), 3.81 (m, 3H), 4.43(m, 1H), 4.86 (m, 2H), 5.43 (d, J=10.8 Hz, 1H), 5.65 (s, 1H), 6.1 (s,1H), 6.54 (d, J=6.8 Hz, 2H), 6.96 (dd, J=8.2 and 5.8 Hz, 2H), 7.129 (m,3H), 7.56 (d, J=8.0 Hz, 1H).

[0083][2-(3,4-Dihydro-1H-pyrazino[1,2-a]indol-2-yl)-1-(4-hydroxy-benzyl)-2-oxo-ethyl]-methyl-carbamicacid tert-butyl ester. Following the general procedure (A) this productwas obtained. m.p. 130-132° C.; [a]=−9.47, c=0.35% in CHCl₃; 1H-NMR(CDCl3): d 1.42 (s, 9H), 2.71 (s, 3H), 2.82 (t, J=4.0 Hz, 2H), 3.96 (m,4H), 4.43 (m, 1H), 4.84 (m, 2H), 5.33 (d, J=10.6 Hz, 1H), 5.43 (t, J=7.2Hz, 1H), 6.34 (dd, J=12.2 and 7.2 Hz, 1H), 6.64 (m, 1H), 7.15 (m, 5H),7.57 (d, J=8.2 Hz, 1H).

[0084][2-(8-Fluoro-3,4-dihydro-1H-pyrazino[1,2-a]indol-2-yl)-1-(4-hydroxy-benzyl)-2-oxo-ethyl]-methyl-carbamicacid tert-butyl ester. Following the general procedure (A) this productwas obtained. m.p. 65-67° C.; [a]=−79.3, c=1% in CHCl₃; 1H-NMR (CDCl3):d 1.41 (s, 9H), 2.84 (s, 3H), 2.96 (m, 2H), 4.15 (m, 4H), 4.84 (t,J=14.6 Hz, 1H), 5.02 (t, J=14.6 Hz, 1H), 5.37 (d, J=8.6 Hz, 1H), 5.53(d, J=6.2 Hz, 1H), 6.26 (dd, J=12.0 and 7.2 Hz, 1H), 6.73 (m, 2H), 7.13(m, 5H).

[0085] General procedure (B) for the synthesis of compounds C1. To asuspension of NaH (24 mg of 55-65% oil suspension, 0.6 mmol, 1.2 equiv.)in dry THF (5 mL) was added B_(i) (0.5 mmol, 1 equiv.). After 10′, theisoquinoline sulfonyl chloride (1 mmole, 2 equiv.) dissolved in dry DCM(2 mL) was added. This mixture was stirred for 18 h at rt. and thenconcentrated in vacuo. The residue was dissolved in a mixture of EtOAc(10 mL) and a saturated aqueous NaHCO₃ (5 mL). After the layers wereseparated, the organic layer was dried (Na₂SO₄), concentrated in vacuoand the residue purified by column chromatography yielded thederivatives C_(i).

[0086]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(benzyl)-piperazine.Following the general procedure (B), this product was obtained as ayellow oil (yield 90%); [a]=-64.4, c=1.15% in CHCl₃. 1H-NMR (CDCl₃) δ:1.31 (s, 9H), 2.72 (m, 4H), 2.90 (m, 2H), 3.48 (m, 7H), 3.70 (m, 2H),5.15 (t, J=7 Hz, 1H), 6.76 (m, J=8.6 Hz, 3H), 7.05 (m, J=8.6 Hz, 3H),7.28 (m, 3H), 7.63 (m, 1H), 8.27 (m, J=7.8 Hz, 2H), 8.54 (d, J=6.1 Hz,1H), 8.79 (d, J=6.1 Hz, 1H), 9.42 (s, 1H).

[0087]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(phenethyl)-piperazine.Following the general procedure (B), this product was obtained as awhite solid (yield 82%); m.p.=58-60° C., [α]=−33.8, c=0.73% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.39 (s, 9H), 2.05 (s, 1H), 2.17 (s, 1H), 2.39 (m,3H), 2.57 (m, 3H), 2.72 (m, 4H), 2.87 (m, 2H), 3.36 (m, 2H), 3.51 (m,1H), 5.15 (t, J=7 Hz, 1H), 6.77 (m, 2H), 7.03 (d, J=8.3 Hz, 2H), 7.18(m, 3H), 7.25 (m, 2H), 7.59 (m, J=8.0 Hz, 1H), 8.25 (m, J=5.8 Hz, 2H),8.53 (d, J=6.2 Hz, 1H), 8.79 (d, J=6.2 Hz, 1H), 9.42 (s, 1H).

[0088]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorophenyl)-piperazine.Following the general procedure (B), this product was obtained as a oil(yield 85%); [a]=-54.1, c=1.31% in CHCl₃. 1H-NMR (CDCl₃) δ: 1.33 (s,9H), 2.73 (s, 3H), 2.91 (m, 6H), 3.51 (m, 4H), 5.17 (t, J=7.2 Hz, 1H),6.77 (m, J=8.6 Hz, 4H), 7.01 (m, J=8.6 Hz, 4H), 7.62 (dd, J=7.6 Hz, 1H),8.26 (m, J=7.6, 2H), 8.52 (d, J=6.1 Hz, 1H), 8.79 (d, J=6.1 Hz, 1H),9.40 (s, 1H).

[0089]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxyarbonyl-N-methyl-tyrosyl]-4-(4-chlorophenyl)-piperazine.Following the general procedure (B), this product was obtained as awhite liquid (yield 86%); [α]=-68.4, c=1% in CHCl₃. 1H-NMR (CDCl₃) δ:1.33 (s, 9H), 1.57 (m, 2H), 2.74 (s, 3H), 3.09 (m, 4H), 3.48 (m, 4H),5.22 (t, J=7 Hz, 1H), 6.77 (m, 4H), 7.10 (t, J=8.6 Hz, 2H), 7.23 (m,2H), 7.61 (t, J=8.6 Hz, 1H), 8.25 (dd, J=6.6 and 6.2 Hz, 2H), 8.54 (d,J=6.2 Hz, 1H), 8.80 (d, J=6.2 Hz, 1H), 9.41 (s, 1H).

[0090]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxyarbonyl-N-methyl-tyrosyl]-4-(4-iodophenyl)-piperazine.Following the general procedure (B), this product was obtained as a foamyellow oil (yield >95%); [α]=-48.8, c=1.22% in CHCl₃. 1H-NMR (CDCl₃) δ:1.34 (s, 9H), 2.73 (s, 3H), 2.98 (m, 6H), 3.51 (m, 4H), 5.21 (t, J=7 Hz,1H), 6.64 (d, J=8.8, 2H), 6.76 (t, J=8.6, 2H), 7.09 (t, J=8.6, 2H), 7.53(d, J=8.8, 2H), 7.61 (m, J=7.2 Hz, 1H), 8.25 (m, J=7.2 Hz, 2H), 8.53 (d,J=6.1 Hz, 1H), 8.80 (d, J=6.1 Hz, 1H), 9.41 (s, 1H).

[0091]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(p-tolyl)piperazine.Following the general procedure (B), this product was obtained as ayellow oil (yield 90%); [α]=−10.9, c=1.34% in CHCl₃. 1H-NMR (CDCl₃) δ:1.33 (s, 9H), 2.05 (s, 3H), 2.74 (s, 3H), 2.82 (m, 2H), 3.04 (m, 4H),3.51 (m, 4H), 5.22 (t, J=7.2 Hz, 1H), 6.79 (t, J=8.4 Hz, 4H), 7.09 (d,J=8.4 Hz, 4H), 7.61 (t, J=7.6 Hz, 1H), 8.26 (m, 2H), 8.53 (d, J=6 Hz,1H), 8.80 (d, J=6 Hz, 1H), 9.41 (s, 1H).

[0092]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl4-(4-methoxyphenyl)-piperazine.Following the general procedure (B), this product was obtained as ayellow oil (yield 82%); [a]=-63.3, c=1.1% in CHCl₃. 1H-NMR (CDCl₃) δ:1.33 (s, 9H), 1.57 (m, 2H), 2.73 (s, 3H), 2.96 (m, 4H), 3.51 (m, 4H),3.76 (s, 3H), 5.21 (t, J=7 Hz, 1H), 6.82 (m, 4H), 7.10 (t, J=8.6 Hz,2H), 7.23 (m, 2H), 7.61 (t, J=8.6 Hz, 1H), 8.25 (dd, J=6.6 and 6.2 Hz,2H), 8.54 (d, J=6.2 Hz, 1H), 8.78 (d, J=6.2 Hz, 1H), 9.42 (s, 1H).

[0093]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(4-nitrophenyl)-piperazine.Following the general procedure (B), this product was obtained as ayellow solid (yield 79%); m.p.=46-47° C., [α]=−58.71, c=1.01% in CHCl₃.1H-NMR (CDCl₃) δ: 1.34 (s, 9H), 2.83 (dd, J=14 and 6.4 Hz, 2H), 2.95 (s,3H), 3.44 (m, 4H), 3.56 (m, 4H), 5.19 (t, J=7.2 Hz, 1H), 6.79 (dd, J=7.2and 3.6 Hz, 4H), 7.10 (d, J=8.6 Hz, 2H), 7.61 (t, J=7.8 Hz, 1H), 8.11(d, J=7.4 Hz, 2H), 8.25 (t, J=8.8 Hz, 2H), 8.51 (d, J=6.2 Hz, 1H), 8.80(d, J=6.2 Hz, 1H), 9.51 (s, 1H).

[0094]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(4-cyanophenyl)-piperazine.Following the general procedure (B), this product was obtained as a foalyellow oil (yield <95%); [a]=+4.21, c=1.4% in CHCl₃. 1H-NMR (CDCl₃) δ:1.34 (s, 9H), 2.74 (s, 3H), 3.09 (m, 6H), 3.49 (m, 4H), 5.22 (t, J=7 Hz,1H), 6.79 (t, J=8.6 Hz, 4H), 7.11 (t, J=8.4 Hz, 3H), 7.51 (d, J=8.6 Hz,1H), 7.63 (t, J=7.6 Hz, 1H), 8.26 (dd, J=6.8 and 4.4 Hz, 2H), 8.51 (d,J=6 Hz, 1H), 8.80 (d, J=6 Hz, 1H), 9.41. (s, 1H).

[0095]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-acetylphenyl)-piperazine.Following the general procedure (B), this product was obtained as a oil(yield >95%); [α]=−51.82, c=1.2% in CHCl₃. 1H-NMR (CDCl₃) δ: 1.35 (s,9H), 2.53 (s, 3H), 2.74 (s, 3H), 3.49 (m, 10H), 5.19 (t, J=7.2 Hz, 1H),6.77 (m, J=8.6, 2H), 6.84 (m, J=8.9 Hz, 2H), 7.10 (t, J=8.6 Hz, 2H),7.62 (t, 1H), 7.89 (d, J=8.9 Hz, 2H), 8.28 (m, J=6.2 Hz, 2H), 8.51 (d,J=6.2 Hz, 1H), 8.80 (d, J=6.2 Hz, 1H), 9.42 (s, 1H).

[0096]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(4-fluorobenzyl)-piperazine.Following the general procedure (B), this product was obtained as abrown oil (yield 77%); [α]=−38.9, c=0.66% in CHCl₃. 1H-NMR (CDCl₃) δ:1.32 (s, 9H), 2.72 (s, 3H), 2.90 (m, 3H), 3.50 (m, 7H), 3.73 (m, 2H),5.15 (t, J=7 Hz, 1H), 6.78 (t, J=8.6 Hz, 2H), 7.03 (m, J=8.6 Hz, 4H),7.25 (m, J=6.6 Hz, 2H), 7.64 (m, 1H), 8.28 (d, J=7.8 Hz, 2H), 8.54 (d,J=6.1 Hz, 2H), 8.81 (d, J=6.2 Hz, 1H), 9.42 (s, 1H).

[0097]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzoyl)-piperazine.Following the general procedure (B), this product was obtained as awhite oil (yield >95%); [α]=−27.4, c=0.74% in CH₂Cl₂. 1H-NMR (CDCl₃) δ:1.35 (s, 9H), 1.62 (m, 5H), 2.50 (m, 3H), 2.72 (s, 3H), 2.90 (m, 3H),3.90 (m, 1H), 4.50 (m, 1H), 5.12 (t, J=6.2 Hz, 1H), 6.76 (d, J=8.4 Hz,2H), 7.08 (m, J=8.6 Hz, 4H), 7.23 (m, 3H), 7.67 (m, 1H), 8.27 (m, J=6.0Hz, 2H), 8.54 (d, J=6.1 Hz, 1H), 8.80 (d, J=6.0 Hz, 1H), 9.42 (s, 1H).

[0098]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(4-nitrobenzyl)-piperazine.Following the general procedure (B), this product was obtained as ayellow oil (yield 54%); [α]=−44.5, c=0.44% in CH₃OH. ¹H-NMR (CDCl₃) δ:1.30 (s, 9H), 2.73 (m, 4H), 2.90 (m, 2H), 3.50 (m, 7H), 3.70 (m, 2H),5.15 (t, J=7 Hz, 1H), 6.79 (t, J=8.3 Hz, 2H), 7.06 (t, J=8.5 Hz, 2H),7.49 (d, J=8.3 Hz, 2H), 7.65 (t, J=7.7 Hz, 1H), 8.18 (d, J=8.3 Hz, 2H),8.29 (d, J=7.7 Hz, 2H), 8.54 (d, J=6.0 Hz, 1H), 8.80 (d, J=6.1 Hz, 1H),9.42 (s, 1H).

[0099]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-fluorophenyl)-piperazine.Following the general procedure (B), this product was obtained as ayellow oil (yield >95%); [α]=−44.23, c=1.04% in CHCl₃. 1H-NMR (CDCl₃) δ:1.34 (s, 9H), 2.75 (s, 3H), 2.92 (m, 6H), 3.52 (m, 4H), 5.22 (t, J=7 Hz,1H), 6.79 (m, 5H), 7.14 (m, 4H), 7.62 (t, J=7.6 Hz, 1H), 8.26 (t, J=7.2Hz, 1H), 8.53 (t, J=6 Hz, 1H), 8.82 (d, J=6 Hz, 1H), 9.41 (s, 1H).

[0100][(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl-4-(2-chlorophenyl)-piperazine.Following the general procedure (B), this product was obtained as a oil(yield >95%); [α]=−40.6, c=1.23% in CHCl₃. 1H-NMR (CDCl₃) δ: 1.34 (s,9H), 2.76 (s, 3H), 2.88 (m, 6H), 3.62 (m, 4H), 5.19 (t, J=7 Hz, 1H),6.79 (t, J=8.6, 2H), 7.05 (m, J=6.2 and 8.6, 4H), 7.22 (d, J=6.2 Hz,1H), 7.37 (d, J=7.9 Hz, 1H), 7.64 (t, 1H), 8.28 (t, J=7, 2H), 8.57 (d,J=6.1 Hz, 1H), 8.80 (d, J=6.1 Hz, 1H), 9.44 (s, 1H).

[0101] 1-[(S)-O-Preparation ofisoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine.Following the general procedure (B), this product was obtained as ayellow oil (yield 72%); [α]=−47.0, c=1.27% in CHCl₃. 1H-NMR (CDCl₃) δ:1.38 (s, 9H), 2.28 (s, 3H), 2.74 (m, 6H), 2.86 (s, 3H), 3.65 (m, 4H),5.26 (t, J=7.2 Hz, 1H), 6.81 (t, J=9.0 and 8.4 Hz, 3H), 7.02 (m, J=8.9and 8.5 Hz, 3H), 7.18 (t, J=7.4 Hz, 2H), 7.72 (t, J=7.7 Hz, 1H), 8.27(m, J=8.4 and 6.1 Hz, 2H), 8.54 (d, J=6 Hz, 1H), 8.82 (d, J=6 Hz, 1H),9.43 (s, 1H).

[0102]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-methoxyphenyl)-piperazineFollowing the general procedure (B), this product was obtained as ayellow oil (yield 64%); [α]=−61.0, c=1.54% in CHCl₃. 1H-NMR (CDCl₃) δ:1.34 (s, 9H), 2.75 (s, 3H), 2.91 (m, 6H), 3.51 (m, 4H), 3.87 (s, 3H),5.20 (t, J=7 Hz, 1H), 6.76 (d, J=8.5, 2H), 6.83 (m, J=6.6, 3H), 7.06 (m,J=8.5, 3H), 7.61 (m, J=6.6 Hz, 1H), 8.27 (m, 2H), 8.54 (d, J=6 Hz, 1H),8.81 (d, J=6 Hz, 1H), 9.42 (s, 1H).

[0103]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(3-chlorophenyl)-piperazine.Following the general procedure (B), this product was obtained as a foamyellow oil (yield >95%); m.p.=79-81° C., [α]=−42.2, c=0.62% in CHCl₃.1H-NMR (CDCl₃) δ: 1.35 (s, 9H), 2.73 (s, 3H), 2.92 (m, 6H), 3.51 (m,4H), 5.21 (t, J=7 Hz, 1H), 6.79 (m, 5H), 7.14 (m, 4H), 7.61 (t, J=7.2Hz, 1H), 8.26 (t, J=7.2 Hz, 1H), 8.53 (d, J=6.2 Hz, 1H), 8.80 (d, J=4.2Hz, 1H), 9.41 (s, 1H).

[0104]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(3-trifluoromethylphenyl)-piperazine.Following the general procedure (B), this product was obtained as awhite solid (yield 75%); m.p.=74-76° C., [α]=−48.9, c=0.76% in CHCl₃.1H-NMR (CDCl₃) δ: 1.35 (s, 9H), 2.74 (s, 3H), 3.01 (m, 6H), 3.65 (m,4H), 5.20 (t, J=7 Hz, 1H), 6.79 (m, J=8.6 Hz, 2H), 7.08 (m, J=8.6 Hz,5H), 7.37 (t, J=7.8 Hz, 1H), 7.66 (m, J=7.8 Hz, 1H), 8.29 (dd, J=8.1 and4.6 Hz, 2H), 8.58 (d, J=6.1 Hz, 1H), 8.81 (d, J=6.1 Hz, 1H), 9.44 (s,1H).

[0105]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(2,3-dimethylphenyl)-piperazine.Following the general procedure (B), this product was obtained as ayellow oil (yield 44%); [α]=−70, c=0.2% in CH₂Cl₂. 1H-NMR (CDCl₃) δ:1.39 (s, 9H), 2.21 (s, 3H), 2.27 (s, 3H), 2.76 (s, 3H), 2.82 (m, 6H),3.58 (m, 4H), 5.20 (t, J=7 Hz, 1H), 6.80 (m, J=8.3 Hz, 3H), 6.95 (m,1H), 7.08 (m, J=8.4 Hz, 3H), 7.66 (m, 1H), 8.26 (m, J=8.4, 2H), 8.55 (d,J=6.1 Hz, 1H), 8.81 (d, J=6.1 Hz, 1H), 9.41 (s, 1H).

[0106]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl-4-(3,4-dichlorophenyl)-piperazine.Following the general procedure (B), this product was obtained as ayellow solid (yield 52%); m.p.=85-87° C., [a]=+12, c=0.5% in CHCl₃.1H-NMR (CDCl₃) δ: 1.34 (s, 9H), 2.73 (s, 3H), 2.92 (m, 6H), 3.51 (m,4H), 5.19 (t, J=7 Hz, 1H), 6.74 (m, 2H), 6.90 (s, 1H), 7.10 (d, J=7.4Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 8.26 (dd, J=7and 3.6 Hz, 1H), 8.54 (t, J=6 Hz, 1H), 8.81 (d, J=6 Hz, 1H), 9.42 (s,1H).

[0107]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(pyridin-2-yl)-piperazine.Following the general procedure (B), this product was obtained as awhite solid (yield 90%); m.p.=56-58° C., [α]=−59.3, c=0.43% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.35 (s, 9H), 2.75 (s, 3H), 3.00 (m, 1H), 3.45 (m,8H), 3.85 (m, 1H), 5.19 (t, J=7 Hz, 1H), 6.69 (m, J=8.4 Hz, 4H), 7.07(t, J=8.4 Hz, 2H), 7.51 (t, J=6.6 Hz, 1H), 7.62 (m, 1H), 8.23 (m, J=7.1Hz, 3H), 8.53 (d, J=6.1 Hz, 1H), 8.89 (d, J=6.2 Hz, 1H), 9.41 (s, 1H).

[0108]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(pyrimidin-2-yl)-piperazine].Following the general procedure (B), this product was obtained as awhite solid (yield 80%); m.p.=104-106° C., [α]=−48.6, c=0.37% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.35 (s, 9H), 2.76 (s, 3H), 3.00 (m, 2H), 3.53 (m,5H), 3.85 (m, 3H), 5.19 (t, J=7 Hz, 1H), 6.54 (m, 1H), 6.78 (t, J=8.4Hz, 2H), 7.08 (t, J=8.4 Hz, 2H), 7.63 (m, 1H), 8.29 (m, 4H), 8.53 (d,J=6.1 Hz, 1H), 8.81 (d, J=6.2 Hz, 1H), 9.42 (s, 1H).

[0109]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(benzyl)-piperidine].Following the general procedure (B), this product was obtained as awhite solid (yield 90%); m.p.=100-102° C., [α]=−39.3, c=0.4% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.31 (s, 9H), 2.72 (m, 4H), 2.90 (m, 2H), 3.48 (m,7H), 3.70 (m, 2H), 5.15 (t, J=7 Hz, 1H), 6.76 (m, J=8.6 Hz, 3H), 7.05(m, J=8.6 Hz, 3H), 7.28 (m, 3H), 7.63 (m, 1H), 8.27 (m, J=7.8 Hz, 2H),8.54 (d, J=6.1 Hz, 1H), 8.79 (d, J=6.1 Hz, 1H), 9.42 (s, 1H).

[0110]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-tyrosyl]-4-(4-fluorophenyl)-piperazine.Following the general procedure (B), this product was obtained as awhite solid (yield 79%); m.p.=87-89° C., [α]=−1.6, c=0.63% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.39 (s, 9H), 2.65 (m, 1H), 2.92 (m, 6H), 3.43 (m,2H), 3.78 (m, 1H),4.76 (m, 1H), 5.33 (d, 1H), 6.82 (m, 4H), 7.01 (m,4H), 7.54 (t, J=7.6 Hz, 1H), 8.22 (dd, J=7.5 and 8.2 Hz, 2H), 8.53 (d,J=6.1 Hz, 1H), 8.80 (d, J=6.1 Hz, 1H), 9.41 (s, 1H).

[0111]1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-tyrosyl]-4-(o-tolyl)-piperazine.Following the general procedure (B), this product was obtained as awhite solid (yield 73%); m.p.=73-75° C., [α]=+22.5, c=1.3% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.39 (s, 9H), 2.27 (s, 3H), 2.42 (m, 1H), 2.75 (m,3H), 2.91 (d, J=6.7 Hz, 2H), 3.15 (m, 1H), 3.51 (m, 3H), 4.80 (m, 1H),5.37 (d, J=8.5 Hz, 1H), 6.80 (d, J=8.5 Hz, 2H), 6.90 (d, J=7.8 Hz, 1H),7.05 (t, J=8.4 Hz, 3H), 7.18 (t, J=7.3 Hz, 2H), 7.54 (t, J=7.8, 1H),8.22 (dd, J=8.2 and 7.3 Hz, 2H), 8.54 (d, J=6.2 Hz, 1H), 8.81 (d, J=6Hz, 1H), 9.41 (s, 1H).

[0112] General procedure for removal the Boc protecting group fromcompounds C_(i). The ester C_(i) (1.5 mmol) was stirred at rt. in amixture of TFA/CH₂Cl₂ (1:1, 5 mL) for 3 h. The volatiles were removed invacuo and the residue was diluted with 5% aqueous NaHCO₃ (5 mL). Theaqueous mixture was extracted with CH₂Cl₂ (3×5 mL) and the combinedorganic extracts were dried (Na₂SO₄) and concentrated in vacuo. Theresidue obtained was used for the next reaction without anypurification.

[0113] General procedure (C) for the synthesis of compounds D1. To astirred solution of the appropriate free amine (0.5 mmol) in dry DCM (5mL) were added Et₃N (70 μL, 0.5 mmol, 1 equiv.) and then dropwiseisoquinolinesulfonyl chloride (1 mmole, 2 equiv.) dissolved in DCM (3mL), under cooling with ice. The reaction mixture obtained was allowedto slowly warm up to rt. and stirred for 18 h. After this time, themixture was diluted with DCM (5 mL) and washed with a saturated aqueousNaHCO₃ (2 mL), water (5 mL) and brine (5 mL). After the layers wereseparated, the organic layer was dried (Na₂SO₄) and concentrated invacuo. The residue obtained, subjected to purification by columnchromatography, furnished the appropriate product D_(i).

[0114] Preparation of1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(benzyl)piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 35%); m.p.=92-94° C., [α]=−33.8, c=0.95% in CHCl₃.1H-NMR (CDCl₃) δ: 1.95 (m, 1H), 2.16 (m, 1H), 2.25 (t, J=4.7 Hz, 2H),2.49 (dd, J=12.4 and 4.6 Hz, 1H), 3.04 (m, 4H), 3.19 (dd, J=10.3 Hz,2H), 3.40 (m, 4H), 5.06 (dd, J=10.3 and 4.5 Hz, 1H), 6.76 (d, J=8.6 Hz,2H), 6.95 (d, J=8.6 Hz, 2H), 7.27 (m, 5H), 7.59 (t, J=7.8 Hz, 1H), 7.68(t, J=7.6 Hz, 1H), 8.25 (m, J=8.2 and 7.7 Hz, 4H), 8.39 (d, J=6.1 Hz,1H), 8.56 (d, J=6.2 Hz, 1H), 8.66 (d, J=6.2 Hz, 1H), 8.83 (d, J=6.1 Hz,1H), 9.35 (s, 1H), 9.43 (s, 1H).

[0115]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(phenethyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 25%); m.p.=98-100° C., [α]=+33.2, c=0.84% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.94 (m, 6H), 2.47 (m, 2H), 2.73 (m, 5H), 3.04 (m,4H), 4.31 (m, 1H), 6.12 (m, 1H), 6.63 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5Hz, 2H), 7.22 (m, 5H), 7.62 (dt, J=7.8 Hz, 2H), 8.23 (m, 5H), 8.51 (d,J=6 Hz, 1H), 8.68 (d, J=6.2 Hz, 1H), 8.80 (d, J=6.2 Hz, 1H), 9.32 (s,1H), 9.41 (s, 1H).

[0116]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-fluorophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 38%); m.p.=110-112° C., [α]=−56.6, c=0.45% in CHCl₃.1H-NMR (CDCl₃) δ: 2.42 (dd, J=12.6 and 6.2 Hz, 1H), 2.63 (m, 1H), 2.89(m, 2H), 3.03 (s, 3H), 3.25 (dd, J=12.6 Hz, 2H) 3.55 (m, 4H), 5.12 (dd,J=12 and 6.2 Hz, 1H), 6.80 (m, J=8.5 Hz, 4H), 6.99 (m, J=8.5 Hz, 4H),7.55 (t, J=7.9 Hz, 1H), 7.71 (t, J=7.9 Hz, 1H), 8.25 (m, J=8 Hz, 4H),8.42 (d, J=6.3 Hz, 1H), 8.52 (d, J=6.3 Hz, 1H), 8.68 (d, J=6.3 Hz, 1H),8.81 (d, J=6.3 Hz, 1H), 9.36 (s, 1H), 9.41 (s, 1H).

[0117]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-chlorophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow oil (yield 61%); [α]=−43.4, c=0.89% in CHCl₃. 1H-NMR (CDCl₃) δ:2.44 (dd, J=12.6 and 6.2 Hz, 2H), 2.92 (m, 4H), 3.00 (s, 3H), 3.57 (m,4H), 5.11 (dd, J=6.6 and 6.2 Hz, 1H), 6.76 (d, J=8.6 Hz, 4H), 6.95 (d,J=8.6 Hz, 2H), 7.23 (d, J=6.6 Hz, 1H), 7.54 (d, J=8 Hz, 1H), 7.70 (t,J=7.8 Hz, 1H), 8.23 (m, 4H), 8.41 (d, J=6 Hz, 1H), 8.49 (d, J=6 Hz, 1H),8.67 (d, J=6.2 Hz, 1H), 8.80 (d, J=6 Hz, 1H), 9.35 (s, 1H), 9.41 (s,1H).

[0118]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(4-iodophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 44%); m.p.=95-97° C., [α]=−46.0, c=0.73% in CHCl₃.1H-NMR (CDCl₃) δ: 2.42 (dd, J=12.6 and 6.2 Hz, 1H), 2.63 (m, 1H), 2.99(m, 5H), 3.22 (m, 2H), 3.55(m, 4H), 5.11 (dd, J=13.6 and 6 Hz, 1H), 6.63(d, J=8.9 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.54(m, J=8.8 and 7.8 Hz, 3H), 7.71 (t, J=7.8 Hz, 1H), 8.24 (m, J=7.6 Hz,4H), 8.42 (d, J=6.3 Hz, 1H), 8.50 (d, J=6.1 Hz, 1H), 8.68 (d, J=6.1 Hz,1H), 8.81 (d, J=6.1 Hz, 1H), 9.36 (s, 1H), 9.41 (s, 1H).

[0119]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(p-tolyl)-piperazine.Following the general procedure, this product was obtained as a foamyellow oil (yield 58%); m.p.=70-72° C., [α]=−41.5, c=0.45% in CHCl₃.1H-NMR (CDCl₃) δ: 2.28 (s, 3H), 2.89 (m, 2H), 3.04 (s, 3H), 3.21 (m,4H), 3.49 (m, 4H), 5.14 (dd, J=12 and 6.2 Hz, 1H), 6.77 (dd, J=6.2 and 3Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 7.49 (t, J=7.8Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 8.13 (d, J=7.4 Hz, 2H), 8.17 (t, J=8.8Hz, 2H), 8.24 (t, J=7.8 Hz, 1H), 8.31 (d, J=7.2 Hz, 1H), 8.41 (d, J=6Hz, 1H), 8.51 (d, J=6.2 Hz, 1H), 8.68 (d, J=6.2 Hz, 1H), 8.81 (d, J=6Hz, 1H), 9.35 (s, 1H), 9.40 (s, 1H).

[0120]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(4-methoxyphenyl)-piperazine.Following the general procedure (C), this product was obtained as awhite solid (yield 47%); m.p.=85-87° C., [α]=−48.4, c=0.94% in CHCl₃.1H-NMR (CDCl₃) δ: 2.48 (dd, J=12 and 4.4 Hz, 2H), 2.83 (m, 4H), 3.16 (s,3H), 3.52 (m, 4H), 3.77 (s, 3H), 5.11 (dd, J=6.6 and 6.2 Hz, 1H), 6.76(m, 6H), 6.96 (d, J=8.4 Hz, 2H), 7.51 (d, J=8 Hz, 1H), 7.69 (t, J=8 Hz,1H), 8.23 (m, 4H), 8.41 (d, J=6.2 Hz, 1H), 8.51 (d, J=6.2 Hz, 1H), 8.67(d, J=6.2 Hz, 1H), 8.80 (d, J=6.2 Hz, 1H), 9.35 (s, 1H), 9.40 (s, 1H).

[0121] 1-[(S)-N,O-bis(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-nitrophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 76%); m.p.=77-79° C., [α]=−86, c=1.02% in CHCl₃.1H-NMR (CDCl₃) δ: 2.34 (dd, J=14 and 6.2 Hz, 2H), 3.01 (s, 3H), 3.28 (m,4H), 3.64 (m, 4H), 5.19 (dd, J=13.8 and 6.2 Hz, 1H), 6.78 (d, J=5.2 Hz,2H), 6.81 (d, J=5.6 Hz, 2H), 6.98 (d, J=8.6 Hz, 2H), 7.59 (t, J=7.8 Hz,1H), 7.73 (t, J=7.8 Hz, 1H), 8.13 (d, J=7.4 Hz, 2H), 8.17 (d, J=7.4 Hz,2H), 8.20 (t, J=8.8 Hz, 1H), 8.23 (t, J=8.8 Hz, 1H), 8.44 (d, J=6.2 Hz,1H), 8.50 (d, J=6.2 Hz, 1H), 8.68 (d, J=6.2 Hz, 1H), 8.80 (d, J=6 Hz,1H), 9.37 (s, 1H), 9.42 (s, 1H).

[0122]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-cyanophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 58%); m.p.=125-127° C., [α]=−67.2, c=0.75% in CHCl₃.1H-NMR (CDCl₃) δ: 2.17 (dd, J=12.6 and 6.2 Hz, 2H), 3.00 (s, 3H), 3.17(m, 4H), 3.69 (m, 4H), 5.11 (dd, J=6.6 and 6 Hz, 1H), 6.80 (m, 4H), 6.97(d, J=6.8 Hz, 2H), 7.52 (d, J=8.6 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 7.72(t, J=7.8 Hz, 1H), 8.30 (m, 4H), 8.41 (d, J=6 Hz, 1H), 8.49 (d, J=6 Hz,1H), 8.67 (d, J=6.2 Hz, 1H), 8.81 (d, J=6 Hz, 1H), 9.37 (s, 1H), 9.42(s, 1H).

[0123]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-acetylphenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 43%); m.p.=82-84° C., [α]=−56.9, c=1.12% in CHCl₃.1H-NMR (CDCl₃) δ: 2.42 (dd, J=12.6 and 6.2 Hz, 1H), 2.53 (s, 3H), 2.90(m, 1H), 3.02 (s, 3H), 3.21 (m, 5H), 3.63 (m, 3H), 5.14 (dd, J=12 and6.2 Hz, 1H), 6.79 (t, J=8.5, 4H), 6.95 (d, J=8.5 Hz, 2H), 7.52 (t, J=7.8Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.89 (d, J=8.9 Hz, 2H), 8.24 (m, J=7.4Hz, 4H), 8.41 (d, J=6.1 Hz, 1H), 8.49 (d, J=6.2 Hz, 1H), 8.68 (d, J=6.2Hz, 1H), 8.79 (d, J=6.1 Hz, 1H), 9.35 (s, 1H), 9.39 (s, 1H).

[0124] Preparation of1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-fluorobenzyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 10%); m.p.=103-105° C., [α]=−21.5, c=0.72% in CHCl₃.1H-NMR (CDCl₃) δ: 1.95 (m, 1H), 2.24 (m, 3H), 2.49 (dd, J=12.4 and 4.6Hz, 1H), 3.04 (m, 4H), 3.14 (m, 2H), 3.38 (m, 4H), 5.06 (dd, J=10.3 and4.5 Hz, 1H), 6.78 (d, J=8.4 Hz, 2H), 6.99 (m, J=8.4 Hz, 4H), 7.22 (m,2H), 7.66 (dt, J=7.8 Hz, 2H), 8.25 (m, 4H), 8.39 (d, J=6.2 Hz, 1H), 8.56(d, J=6 Hz, 1H), 8.66 (d, J=6.3 Hz, 1H), 8.83 (d, J=6.2 Hz, 1H), 9.36(s, 1H), 9.44 (s, 1H).

[0125]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-fluorobenzoyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 18%); m.p.=124-126° C., [α]=−37.8, c=0.82% inCH₂Cl₂. 1H-NMR (CDCl₃) δ: 2.49 (m, 1H), 2.79 (m, 1H), 3.03 (s, 3H), 3.28(m, 6H), 3.57 (m, 2H), 5.07 (dd, J=10.9 and 4.3 Hz, 1H), 6.79 (d, J=8.4Hz, 2H), 6.97 (d, J=8.5 Hz, 2H), 7.12 (t, J=8.6 Hz, 2H), 7.44 (m, 2H),7.72 (t, J=7.9 Hz, 2H), 8.31 (m, 5H), 8.54 (d, J=5.9 Hz, 1H), 8.68 (d,J=6 Hz, 1H), 8.84 (d, J=6 Hz, 1H), 9.38 (s, 1H), 9.45 (s, 1H).

[0126]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(4-nitrobenzyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 40%); m.p.=145-147° C., [α]=−28.4, c=0.37% in CHCl₃.1H-NMR (CDCl₃) δ: 1.95 (m, 1H), 2.27 (m, 3H), 2.49 (dd, J=12.4 and 4.6Hz, 1H), 2.02 (m, 4H), 3.21 (dd, J=10.3 Hz, 2H), 3.49 (m, 4H), 5.12 (dd,J=10.3 and 4.5 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.6 Hz, 2H),7.48 (d, J=8.4 Hz, 2H), 7.68 (m, J=8.3 Hz, 2H), 8.18 (d, J=8.6 Hz, 3H),8.30 (m, J=7.5 Hz, 3H), 8.40 (d, J=6 Hz, 1H), 8.55 (d, J=6.2 Hz, 1H),8.67 (d, J=6 Hz, 1H), 8.83 (d, J=6.3 Hz, 1H), 9.37 (s, 1H), 9.45 (s,1H).

[0127]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(2-fluorophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 76%); m.p.=133-135° C., [α]=−58.4, c=0.44% in CHCl₃.1H-NMR (CDCl₃) δ: 2.49 (m, 2H), 3.06 (s, 3H), 3.22 (m, 4H), 3.63 (m,4H), 5.11 (dd, J=13.6 and 6 Hz, 1H), 6.79 (m, 4H), 7.00 (m, 4H), 7.57(t, J=8.2 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 8.25 (m, 4H), 8.41 (d, J=6.2Hz, 1H), 8.52 (d, J=6.2 Hz, 1H), 8.67 (d, J=6.2 Hz, 1H), 8.81 (d, J=6.2Hz, 1H), 9.36 (s, 1H), 9.42 (s, 1H).

[0128]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(2-chlorophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 58%); m.p.=84-86° C., [α]=−39.2, c=0.92% in CHCl₃.1H-NMR (CDCl₃) δ: 2.48 (m, J=12.4 and 4.6 Hz, 2H), 2.83 (m, 2H), 3.07(s, 3H), 3.23 (t, J=10.4 Hz, 2H), 3.58 (m, 4H), 5.12 (dd, J=10.3 and 4.5Hz, 1H), 6.77 (d, J=8.6 Hz, 2H), 6.97 (m, J=8.6 Hz, 4H), 7.23 (d, J=7.8Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.71 (t, J=7.7Hz, 1H), 8.25 (m, J=8.3 and 7.4 Hz, 4H), 8.42 (d, J=6.2 Hz, 1H), 8.54(d, J=6 Hz, 1H), 8.68 (d, J=5.9 Hz, 1H), 8.82 (d, J=6.2 Hz, 1H), 9.37(s, 1H), 9.43 (s, 1H).

[0129]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 58%); m.p.=84-86° C., [α]=−39.2, c=0.92% in CHCl₃.1H-NMR (CDCl₃) δ: 2.28 (s, 3H), 2.35 (m, 1H), 2.49 (dd, J=12.4 and 4.6Hz, 1H), 2.68 (m, 2H), 3.06 (s, 3H), 3.30 (m, 2H), 3.58 (m, 4H), 5.12(dd, J=10.3 and 4.5 Hz, 1H), 6.81 (t, J=9.0 and 8.4 Hz, 3H), 7.02 (m,J=8.9 and 8.5 Hz, 3H), 7.18 (t, J=7.4 Hz, 2H), 7.56 (t, J=7.7 Hz, 1H),7.72 (t, J=7.7 Hz, 1H), 8.27 (m, J=8.4 and 6.1 Hz, 4H), 8.42 (d, J=6.2Hz, 1H), 8.54 (d, J=6 Hz, 1H), 8.68 (d, J=6.2 Hz, 1H), 8.82 (d, J=6 Hz,1H), 9.37 (s, 1H), 9.43 (s, 1H).

[0130]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(2-methoxyphenyl)-piperazine.Following the general procedure(C), this product was obtained as ayellow solid (yield 10%); m.p.=85-87° C., [α]=−29.8, c=0.45% in CHCl₃.1H-NMR (CDCl₃) δ: 2.51 (dd, J=12.6 and 6.2 Hz, 1H), 2.62 (m, 1H), 2.87(m, 2H), 3.07 (s, 3H), 3.22 (m, 2H), 3.56 (m, 4H), 3.87 (s, 3H), 5.15(dd, J=13.6 and 6 Hz, 1H), 6.76 (d, J=8.6 Hz, 2H), 6.97 (m, J=7.9 Hz,4H), 7.30 (m, 1H), 7.63 (m, 3H), 8.11 (d, J=8.1 Hz, 1H), 8.27 (m, J=7.3Hz, 3H), 8.44 (m, 1H), 8.54 (d, J=6 Hz, 1H), 8.75 (m, 2H), 9.40 (m, 2H).

[0131]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(3-chlorophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 67%); m.p.=138-140° C., [α]=−58.8, c=0.6% in CHCl₃.1H-NMR (CDCl₃) δ: 2.42 (m, 2H), 2.99 (s, 3H), 3.22 (m, 4H), 3.59 (m,4H), 5.12 (dd, J=12 and 6.2 Hz, 1H), 6.79 (m, 4H), 6.89 (m, 3H), 7.21(t, J=8 Hz, 1H), 7.54 (t, J=8 Hz, 1H), 7.72 (t, J=8 Hz, 1H), 8.26 (m,4H), 8.42 (d, J=6.2 Hz, 1H), 8.51 (d, J=6.2 Hz, 1H), 8.68 (d, J=6.2 Hz,1H), 8.81 (d, J=6.2 Hz, 1H), 9.37 (s, 1H), 9.42 (s, 1H).

[0132]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(3-trifluoromethylphenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 20%); m.p.=81-83° C., [α]=−61.5, c=0.4% in CHCl₃.1H-NMR (CDCl₃) δ: 2.48 (dd, J=12 and 4.4 Hz, 1H), 2.75 (m, 1H), 2.93 (m,5H), 3.30 (m, 2H), 3.62 (m, 4H), 5.11 (dd, J=6.6 and 6.2 Hz, 1H), 6.78(d, J=8.6 Hz, 2H), 6.99 (m, J=8.6 Hz, 4H), 7.15 (d, J=7.8 Hz, 1H), 7.40(t, J=8.8 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 8.23(m, 4H), 8.43 (d, J=6 Hz, 1H), 8.51 (d, J=6.3 Hz, 1H), 8.68 (d, J=6.4 Hz1H), 8.80 (d, J=6 Hz 1H), 9.36 (s, 1H), 9.41 (s, 1H).

[0133]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(2,3-dimethylphenyl)-piperazine.Following the general procedure (C), this product was obtained as abrown solid (yield 21%); m.p.=174-176° C., [α]=−17.5, c=1.91% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 2.19 (s, 3H), 2.27 (s, 3H), 2.49 (dd, J=12.4 and 4.6Hz, 1H), 2.68 (m, 3H), 3.06 (s, 3H), 3.25 (m, 2H), 3.58 (m, 4H), 5.12(dd, J=10.3 and 4.5 Hz, 1H), 6.76 (m, J=8.7 Hz, 3H), 7.03 (m, J=8.7 Hz,4H), 7.56 (t, J=7.7 Hz, 1H), 7.71 (t, J=7.7 Hz, 1H), 8.26 (m, J=7 Hz,4H), 8.44 (d, J=6.1 Hz, 1H), 8.54 (d, J=6.2 Hz, 1H), 8.68 (d, J=6.2 Hz,1H), 8.82 (d, J=6 Hz, 1H), 9.36 (s, 1H), 9.42 (s, 1H).

[0134]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosy]l-4-(3,4-dichlorophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 64%); m.p.=130-132° C., [α]=−73.4, c=0.44% in CHCl₃.1H-NMR (CDCl₃) δ: 2.96 (m, 2H), 3.02 (s, 3H), 3.41 (m, 4H), 3.63 (m,4H), 5.16 (dd, J=13.6 and 6 Hz, 1H), 6.80 (m, 4H), 6.94 (t, J=8.4 Hz,3H), 7.57 (t, J=8 Hz, 1H), 7.72 (t, J=8 Hz, 1H), 8.22 (m, 4H), 8.44 (d,J=6 Hz, 1H), 8.52 (d, J=6 Hz, 1H), 8.66 (d, J=6 Hz, 1H), 8.81 (d, J=6Hz, 1H), 9.37 (s, 1H), 9.42 (s, 1H).

[0135]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(pyridin-2-yl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 48%); m.p.=183-185° C., [α]=−55.8, c=0.41% inCH₂Cl₂. 1H-NMR (CDCl₃) δ: 2.46 (dd, J=12.7 and 4.3 Hz, 1H), 2.91 (m,1H), 3.05 (s, 3H), 3.21 (m, J=10.6 Hz, 3H), 3.42 (m, 3H), 5.09 (dd,J=10.4 and 4.4 Hz, 1H), 6.60 (d, J=8.6 Hz, 1H), 6.70 (m, J=8.4 Hz, 3H),6.96 (d, J=8.4 Hz, 2H), 7.53 (m, 2H), 7.70 (t, J=7.8 Hz, 1H), 8.12 (d,J=7.3 Hz, 1H), 8.22 (m, 3H), 8.30 (d, J=7.3 Hz, 1H), 8.41 (d, J=6.2 Hz,1H), 8.51 (d, J=6.2 Hz, 1H), 8.67 (d, J=6.3 Hz, 1H), 8.80 (d, J=6.1 Hz,1H), 9.35 (s, 1H), 9.40 (s, 1H).

[0136]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(pyrimidin-2-yl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 32%); m.p.=187-189° C., [α]=−54.6, c=0.76% inCH₂Cl₂. 1H-NMR (CDCl₃) δ: 2.46 (dd, J=12.7 and 4.3 Hz, 1H), 3.00 (m,1H), 3.06 (s, 3H), 3.41 (m, J=10.4 Hz, 6H), 3.80 (m, 2H), 5.09 (dd,J=10.4 and 4.4 Hz, 1H), 6.56 (t, J=8.6 Hz, 1H), 6.74 (d, J=8.5 Hz, 2H),6.96 (d, J=8.5 Hz, 2H), 7.57 (t, J=7.8 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H),8.21 (m, J=7.6 Hz, 4H), 8.33 (m, 2H), 8.40 (d, J=6.3 Hz, 1H), 8.52 (d,J=6.1 Hz, 1H), 8.67 (d, J=6 Hz, 1H), 8.82 (d, J=6 Hz, 1H), 9.35 (s, 1H),9.41 (s, 1H).

[0137]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]4-(benzyl)-piperidine.Following the general procedure (C), this product was obtained as ayellow solid (yield 35%); m.p.=131-133° C., [α]=−24, c=0.42% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 1.50 (m, 2H), 2.39 (m, 6H), 2.70 (m, 1H), 3.04 (s,3H), 3.25 (m, 2H), 3.80 (m, 1H), 4.40 (m, 1H), 5.10 (m, 1H), 6.73 (m,1H), 6.88 (d, J=8.6 Hz, 2H), 7.05 (m, 3H), 7.24 (m, 3H), 7.68 (m, 2H),8.26 (m, 4H), 8.41 (d, J=6.1 Hz, 1H), 8.56 (d, J=6.2 Hz, 1H), 8.68 (d,J=6.2 Hz, 1H), 8.82 (d, J=6 Hz, 1H), 9.35 (s, 1H), 9.43 (s, 1H).

[0138]1-[(S)-N,O-bis-(isoquinolinesulfonyl)tyrosyl]-4-(4-fluorophenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 50%); m.p.=145-147° C., [α]=+47.7, c=0.62% inCH₂Cl₂. 1H-NMR (CDCl₃) δ: 2.22 (m, 2H), 2.50 (m, 4H), 3.06 (m, 3H), 3.25(m, 1H), 4.35 (m, 1H) 5.99 (d, 1H), 6.65 (d, J=8.4 Hz, 2H), 6.78 (m,2H), 6.88 (d, J=8.5 Hz, 2H), 6.99 (t, J=8.5 Hz, 2H), 7.58 (m, 2H), 8.16(t, J=8 Hz, 2H), 8.27 (t, J=6.5 Hz, 3H), 8.51 (d, J=6.3 Hz, 1H), 8.70(d, J=6.3 Hz, 1H), 8.82 (d, J=6 Hz, 1H), 9.30 (s, 1H), 9.41 (s, 1H).

[0139]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-tyrosyl]4-(o-tolyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 88%); m.p.=132-134° C., [α]=+80.3, c=1% in CH₂Cl₂.1H-NMR (CDCl₃) δ: 2.24 (s, 3H), 2.36 (m, 3H), 2.54 (m, 1H), 2.80 (d,J=7.2 Hz, 2H), 2.93 (m, 1H), 3.06 (m, 1H), 3.25 (m, 2H), 4.35 (m, J=7.5Hz, 1H), 6.09 (d, J=9.1 Hz, 1H), 6.4 (d, J=8.3 Hz, 2H), 6.85 (m, J=8.6and 7.8 Hz, 3H), 7.03 (t, J=7.4 Hz, 1H), 7.18 (m, 2H), 7.55 (t, J=7.9Hz, 1H), 7.63 (t, J=7.7 Hz, 1H), 8.24 (m, J=7.5 Hz, 5H), 8.52 (d, J=6Hz, 1H), 8.69 (d, J=6.2 Hz, 1H), 8.82 (d, J=6 Hz, 2H), 9.33 (s, 1H),9.41 (s, 1H).

[0140] Preparation of 1-[(S)-N,O-bis(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-amino-phenyl)-piperazine.Following the general procedure (C), this product was obtained as ayellow solid (yield 45%); m.p.=80-82° C., [α]=−48,4 c=0.90% in CHCl₃.1H-NMR (CDCl₃) δ: 2.48 (m, 2H), 2.83 (m, 4H), 3.16 (s, 3H), 3.52 (m,4H), 4.00 (m, 2H), 5.11 (dd, J=6.6 and 6.2 Hz, 1H), 6.28 (d, J=8.3 Hz,2H), 6.34 (d, J=8.3 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 6.96 (d, J=8.4 Hz,2H), 7.51 (d, J=8 Hz, 1H), 7.69 (t, J=8 Hz, 1H), 8.23 (m, 4H), 8.41 (d,J=6.2 Hz, 1H), 8.51 (d, J=6.2 Hz, 1H), 8.67 (d, J=6.2 Hz, 1H), 8.80 (d,J=6.2 Hz, 1H), 9.35 (s, 1H), 9.40 (s, 1H).

[0141]1,2,3,4-Tetrahydro-2-[(S)-N,O-bis(isoquinolinesulfonyl)-tyrosyl]-1,4-pyrazino[1,2-a]indole.Following the general procedure C this product was obtained. m.p. 83-85°C.; [α]=+8.0, c=0.5% in CHCl₃; 1H-NMR (CDCl₃) d 2.86 (m, 5H), 3.45 (m,2H), 3.64 m, 1H), 4.28 (m, 2H), 6.02 (d, J=9.4 Hz, 1H), 6.1 (t, J=14.6Hz, 1H), 6.72 (m, 3H), 6.94 (m, 2H), 7.22 (m, 2H), 7.37 (m, 2H), 7.61(t, J=8.2 Hz, 1H), 8.06 (m, 5H), 8.46 (d, J=6 Hz, 1H), 8.69 (m, 1H),9.08 (s, 1H), 9.35 (s, 1H).

[0142]1,2,3,4-Tetrahydro-2-[(S)-N,O-bis(isoquinolinesulfonyl)-N-methyl-tyrosyl]-1,4-pyrazino[1,2-a]indole.Following the general procedure C this product was obtained. m.p.110-112° C.; [α]=−4.5, c=0.58% in CHCl₃; 1H-NMR (CDCl₃): d 2.53 (m, 1H),3.02 (s, 3H), 3.12 (m, 1H), 3.59 (m, 5H), 4.57 (dd, J=8.8 and 6 Hz, 1H),4.86 (d, 8.8 Hz, 1H), 5.12 (m, 1H), 6.28 (d, J=9.0 Hz, 1H), 6.68 (t,J=6.8 Hz, 2H), 6.96 (t, J=6.8 Hz, 2H), 7.24 (m, 3H), 7.39 (q, J=7.2 Hz,2H), 7.56 (t, J=7.8 Hz, 1H), 8.11 (m, 5H), 8.46 (d, J=6.2 Hz, 1H), 8.77(t, J=4.2 Hz, 1H), 9.16 (s, 1H), 9.28 (s, 1H).

[0143]1,2,3,4-Tetrahydro-2-[(S)-N,O-bis(isoquinolinesulfonyl)-N-methyl-tyrosyl]-8-fluoro-1,4-pyrazino[1,2-a]indole.Following the general procedure C this product was obtained. m.p.105-107° C.; [α]=−37, c=0.58% in CHCl₃; 1H-NMR (CDCl₃): d 2.53 (m, 1H),3.02 (s, 3H), 3.24 (m, 1H), 3.69 (m, 5H), 4.64 (dd, J=9.2 and 6.2 Hz,1H), 4.88 (d, 8.8 Hz, 1H), 5.12 (m, 1H), 6.28 (d, J=9.0 Hz, 1H), 6.68(t, J=9.0 Hz, 2H), 6.96 (m, 3H), 7.45 (t, J=7.8 Hz, 1H), 7.58 (t, J=7.8Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 8.16 (m, 5H), 8.46 (d, J=6.0 Hz, 1H),8.64 (d, J=4.2 Hz, 1H), 8.80 (t, J=6.4 Hz, 1H), 9.20 (s, 1H), 9.30 (s,1H).

[0144] Changes in plasma membrane permeability. ATP-dependent increasesin plasma membrane permeability were measured with the extracellularfluorescent tracer ethidium bromide (Molecular Probes, Inc., Eugene,Oreg.). For ethidium bromide uptake cells were incubated in athermostat-controlled fluorometer cuvette (37° C.) for 20 min in thedark at a concentration of 10⁶ cells/ml in the presence of 20 mMethidium bromide and challenged with 1 mM ATP. Cell suspension wasincubated with KN62 or synthesized compounds (25 nM-5000 nM) for 5 minat 37° C. before fluorimetric analysis in a stirred cuvette at 37° C.Fluorescence changes were monitored at the wavelength pair 360/580 nm.After several washings to remove the extracellular dye, cells wereanalyzed with an inverted fluorescence microscope (Olympus IMT-2,Olympus Optical Co. Ltd., Tokyo, Japan). All experiments were repeatedthree times.

[0145] Ca²⁺ measurements. Changes in Ca²⁺ were measured with thefluorescent indicator fura-2/AM (Molecular Probes, Inc., Eugene, Oreg.)as described previously.³² Briefly, cells were loaded with 4 mM offura-2/AM and incubated in a thermostat-controlled (37° C.) andmagnetically stirred fluorometer cuvette (model LS50, Perkin-Elmer Ltd.,Beaconsfield, UK). Intracellular Ca²⁺ concentration was determined withthe 340/380 excitation ratio at an emission wavelength of 500 nM. Allexperiments were repeated three times.

[0146] Cytokine release. IL-1β release was measured in macrophagemonolayers primed for two h with bacterial endotoxin(lipopolysaccharide, LPS) at the concentration of 10 μg/ml, and thestimulated with 3 mM ATP for 30 min. Inhibitors, when used, were added 5min prior to ATP. Supernatants were centrifuged for 5 min at 900 g toremove floating cells and were assayed for IL-1β content by ELISA (R&DSystems, Minneapolis, Minn., USA). TABLE I KN62 511-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 5.76tyrosyl]-4-(4-nitrophenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 101tyrosyl]-4-(4-aminophenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 104.7tyrosyl]-4-(4-chlorophenyl)-piperazine]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 131.8tyrosyl]-4-(4-methoxy-phenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 21tyrosyl]-4-benzylpiperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 70.79tyrosyl]-4-(4-acetylphenyl)-piperazine]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 1.33tyrosyl]-4-(4-fluorophenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 175.8tyrosyl]-4-(4-iodophenyl)-piperazine]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 13.48tyrosyl]-4-(p-tolyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 15.84tyrosyl]-4-(2-chlorophenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 84.13tyrosyl]-4-(2-methoxy-phenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 97.74tyrosyl]-4-(4-cyanophenyl)-piperazine]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 31.15tyrosyl]-4-(3-trifluoromethyl-phenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 12.3tyrosyl]-4-(4-nitrobenzyl)-piperazine]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 18.53tyrosyl]-4-(2-fluorophenyl)-piperazine]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 5.8tyrosyl]-4-(4-fluorobenzyl)-piperazine]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 33.89tyrosyl]-4-(3,4-dichloro-phenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 14.13tyrosyl]-4-(3-chlorophenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 15.1tyrosyl]-4-o-tolyl-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)tyrosyl]-4-(4- 6.02fluorophenyl)-piperazine 1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-170 tyrosyl]-4-(pyridin-2-yl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 79.8tyrosyl]-4-(pyrimidin-2-yl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 380.2tyrosyl]-4-(4-fluorobenzoyl)-piperazine]1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 65.31tyrosyl]-4-benzylpiperidine1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 599.8tyrosyl]-4-phenethyl-piperazine1-[(S)-N,O-bis-(3-pyridinesulfonyl)-N-methyl-tyrosyl]- 9554-phenyl-piperazine1-[(S)-N,O-bis-(3-pyridinesulfonyl)-N-methyl-tyrosyl]- 91204-(2-methylphenyl)-piperazine1-[(S)-N,O-bis-(isoquinolinesulfonyl)tyrosyl]-4-(o- 28.84tolyl)-piperazine 1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl- 1122tyrosyl]-4-(2,3-dimethyiphenyl)-piperazine

What is claimed is:
 1. A compound of the formula

wherein R₁ and R₂ are independently hydrogen, C1-C4 alkyl, C1-C4substituted alkyl, C1-C4 alkoxy, C1-C4 substituted alkoxy, C1-C4 acyl,halogen, cyano, nitro, amino, alkylamino, or dialkylamino; R₃, R₄, R₅,R₆, R₇, and R₈ are independently CH or nitrogen; R9 is hydrogen ormethyl; R10 is C═O or (CH2)_(n); where n is 0, 1, 2, 3, or 4; R₁₁ andR₁₂ are independently nitrogen or CH; X₁ and X₂ are independentlyhydrogen, deuterium, tritium or halogen; and X₃ is nitrogen or CH; 2.The pharmaceutically acceptable salts of the compounds of claim [1]. 3.A compound of claim [1] wherein R1 is methyl substituted at theortho-position; R₂ is hydrogen; R₃ and R₈ are each nitrogen; R₄, R₅, R₆,and R₇, are each CH; R₉ is methyl; R₁₀ is (CH2)_(n) where n is 0; R₁₁and R₁₂ are each CH; X₁ and X₂ are each tritium; and X₃ is nitrogen. 4.The compounds of claim [1] wherein R₁ and R₂ are independently hydrogen;R₃ and R₈ are independently nitrogen; R₄, R₅, R₆, and R₇ areindependently CH; and R₁₁, R₁₂, and X₃ are independently CH.
 5. Thecompounds of claim [1] wherein R₃ and R₈ are independently N and whereR₄, R₅, R₆, and R₇ are independently CH.
 6. The compound of claim [1]wherein R₃, R₅, R₆, and R₈ are independently CH, and where R₄ and R₇ areindependently nitrogen.
 7. The compound of claim [1] wherein R₃, R₄, R₇,and R₈ are independently nitrogen and where R₅ and R₆ are independentlyCH.
 8. The compound of claim [1] wherein R₃, R₅, R₆, and R₈ areindependently nitrogen and where R₄ and R₇ are independently CH.
 9. Thecompound of claim [1] wherein R₁ is hydrogen, R₂ is hydrogen, and R₁₀ is(CH2)_(n) wherein n is equal to
 1. 10. The compound of claim [1] whereinR₁ is hydrogen, R₂ is hydrogen, and R₁₀ is (CH2)_(n) wherein n is equalto
 2. 11. The compound of claim [1] wherein R₁ is a fluoro-group in thepara-position and R₂ is hydrogen.
 12. The compound of claim [1] whereinR₁ is a methyl-group in the para-position and R₂ is hydrogen.
 13. Thecompound of claim [1] wherein R₁ is a nitro-group in the para-positionand R₂ is hydrogen.
 14. The compound of claim [1] wherein R₁ is amethyl-group in the ortho-position and R₂ is hydrogen.
 15. The compoundof claim [1] wherein R₁ is a fluoro-group in the ortho-position and R₂is hydrogen.
 16. The compound of claim [1] wherein R₁ is a chloro-groupin the ortho-position and R₂ is hydrogen.
 17. The compound of claim [1]wherein R₁ is a chloro-group in the para-position and R₂ is hydrogen.18. The compound of claim [1] wherein R₁ is an iodo-group in thepara-position and R₂ is hydrogen.
 19. The compound of claim [1] whereinR₁ is a methoxy-group in the para-position and R₂ is hydrogen.
 20. Thecompound of claim [1] wherein R₁ is a cyano-group in the para-positionand R₂ is hydrogen.
 21. The compound of claim [1] wherein R₁ is anacetyl-group in the para-position and R₂ is hydrogen.
 22. The compoundof claim [1] wherein R₁ is a methoxy-group in the ortho-position and R₂is hydrogen.
 23. The compound of claim [1] wherein R₁ is a methyl-groupin the ortho-position and R₂ is a methyl-group in the meta-position. 24.The compound of claim [1] wherein R₁ is a chloro-group in themeta-position and R₂ is hydrogen.
 25. The compound of claim [1] whereinR₁ is a trifluoromethyl-group in the meta-position and R₂ is hydrogen.26. The compound of claim [1] wherein R₁ is a chloro-group in themeta-position and R₂ is a chloro-group in the para position.
 27. Thecompound of claim [1] wherein R₁ and R₂ are independently hydrogen, R₁₁is nitrogen, and R₁₂ is CH.
 28. The compound of claim [1] wherein R₁ andR₂ are independently hydrogen and R₁₁ and R₁₂ are independentlynitrogen.
 29. The compound of claim [1] wherein R₁ is an amino-group inthe para-position and R₂ is hydrogen.
 30. A compound of the formula

wherein: R₁ is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 acyl, halogen,cyano, nitro, amino, alkylamino, or dialkylamino; R₉ is hydrogen ormethyl; and X₁ and X₂ are independently hydrogen, deuterium, tritium, orhalogen.
 31. The pharmaceutically acceptable salts of the compounds ofclaim [30].
 32. A compound of the formula

wherein: R₁ and R₂ are independently hydrogen, C1-C4 alkyl, C1-C4alkoxy, C1-C4 acyl, halogen, cyano, nitro, amino, alkylamino, ordialkylamino; R₉ is hydrogen or methyl; X₁ and X₂ are independentlyhydrogen, deuterium, tritium, or halogen; and X₃ is CH or nitrogen. 33.The pharmaceutically acceptable salts of claim [32].
 34. A compound ofthe formula

wherein: R₁ and R₂ are independently hydrogen, C1-C4 alkyl, C1-C4alkoxy, halogen, cyano, nitro, or amino; R₃, R₄, R₅, R₆, R₇, and R₈ areindependently CH or nitrogen; n is 0, 1, 2, 3, 4; and with the provisothat when n is 0 either R₁ or R₂ is not hydrogen.
 35. The salts of thecompounds of claim [34] that are pharmaceutically acceptable.
 36. Thecompounds of claim [34] wherein R₃ and R₈ are independently N and whereR₄, R₅, R₆, and R₇ are independently CH.
 37. The compounds of claim [34]wherein R₃, R₅, R₆, and R₈ are independently CH, and where R₄ and R₇ areindependently nitrogen.
 38. The compounds of claim [34] wherein R₃, R₄,R₇, and R₈ are independently nitrogen and where R₅ and R₆ areindependently CH.
 39. The compounds of claim [34] wherein R₃, R₅, R₆,and R₈ are independently nitrogen and where R₄ and R₇ are independentlyCH.
 40. The compounds of claim [34] wherein R₁ is hydrogen, R₂ ishydrogen, and n is equal to
 1. 41. The compounds of claim [34] whereinR₁ is a fluoro-group in the para-position and R₂ is hydrogen.
 42. Thecompounds of claim [34] wherein R₁ is a methyl-group in thepara-position and R₂ is hydrogen.
 43. The compounds of claim [34]wherein R₁ is a nitro-group in the para-position and R₂ is hydrogen. 44.The compounds of claim [34] wherein R₁ is a methyl-group in theortho-position and R₂ is hydrogen.
 45. The compounds of claim [34]wherein R₁ is a fluoro-group in the ortho-position and R₂ is hydrogen.46. The compounds of claim [34] wherein R₁ is a chloro-group in theortho-position and R₂ is hydrogen.
 47. The compounds of claim [34]wherein R₁ is a chloro-group in the meta-position and R₂ is hydrogen.48. The compounds of claim [34] wherein R₁ is a chloro-group in themeta-position and R₂ is a chloro-group in the para position.
 49. Amethod of identifying tumor cells rich in purinergic P2X7 receptors in amammal, comprising administering to the mammal an amount of a compoundof claim [1] sufficient to label the purinergic receptors.
 50. Themethod of claim [49] wherein the compound is methyl substituted at theortho-position; R₂ is hydrogen; R₃ and R₈ are each nitrogen; R₄, R₅, R₆,and R₇, are each CH; R₉ is methyl; R₁₀ is (CH2)_(n) where n is 0; R₁₁and R₁₂ are each CH; X₁ and X₂ are each tritium; and X₃ is nitrogen. 51.A method of treating a medical condition in a mammal, comprising theadministration to the mammal in need thereof, of an effective amount ofa compound of claim [1], [30], [32], or [34].
 52. The method of claim[51] wherein the compound is one of the pharmaceutically acceptablesalts of the compounds of claim [1].
 53. The method of claim [51]wherein the compound one of the pharmaceutically acceptable salts of thecompounds of claim [30].
 54. The method of claim [51] wherein thecompound is one of the pharmaceutically acceptable salts of thecompounds of claim [32].
 55. The method of claim [51] wherein thecompound is one of the pharmaceutically acceptable salts of thecompounds of claim [34].
 56. The method of claim [51] wherein the mammalis a human.
 57. The method of claim [51] wherein the medical conditionis an inflammatory disease.
 58. The method of claim [51] wherein themedical condition is a disease of the immune system.
 59. The method ofclaim [51] wherein the medical condition is rheumatoid arthritis. 60.The method of claim [51] wherein the medical condition is tuberculosis.61. The method of claim [51] wherein the medical condition is sterility.62. The method of claim [51] wherein the medical condition isinflammatory bowel disease.
 63. The method of claim [51] wherein themedical condition is lupus erythematosus.
 64. The method of claim [51]wherein the medical condition is the suppression of the immune responsein a patient in need of an organ transplant.
 65. The method of claim[51] wherein the medical condition is cancer in which the tumor cellsare rich in P2X₇ receptors.
 66. The method of claim [65] furthercomprising co-administering a cytotoxic agent.
 67. The method of claim[66] wherein the cytotoxic agent is a topoisomerase-II inhibitor. 68.The method of claim [67] wherein the topoisomerase-II inhibitor isselected from the list consisting of etoposide (VP-16), podophyllotoxin,and teniposide (VM-26).
 69. The method of claim [51] wherein the medicalcondition is a wound.
 70. The method claim of claim [69] wherein themedical condition is a chronic wound.
 71. A method of inducing apoptosisin neoplastic cells in a patient comprising administering to thatpatient a compound of claim [1], [30], [32], or [34] in a pharmaceuticalcarrier.
 72. The method of claim [71] further comprisingco-administering a cytotoxic agent.
 73. The method of claim [72] whereinthe cytotoxic agent is a topoisomerase-II inhibitor.
 74. The method ofclaim [73] wherein the topoisomerase-II inhibitor is selected from thelist consisting of etoposide (VP-16), podophyllotoxin, and teniposide(VM-26).
 75. A compound selected from the group of tyrosyl piperazinederivatives consisting of: a.(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-nitrophenyl)-piperazine;b.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(p-tolyl)-piperazine;c.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-chlorophenyl)-piperazine;d.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorophenyl)-piperazine;e.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3,4-dichlorophenyl)-piperazine;b.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-cyanophenyl)-piperazine;c.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-chlorophenyl)-piperazine;d.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-methoxyphenyl)-piperazine;e. 1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-benzyl-piperazine;f.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-phenethylpiperazine;g.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-iodophenyl)-piperazine;h.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-acetylphenyl)-piperazine;i.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzyl)-piperazine;j.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzoyll)-piperazine;k.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-nitrobenzyl)-piperazine;l.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-fluorophenyl)-piperazine;m.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine;n.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-methoxyphenyl)-piperazine;o.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3-chlorophenyl)-piperazine;p.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3-trifluoromethylphenyl)-piperazine;q.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2,3-dimethylphenyl)-piperazine;r.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(pyridin-2-yl)-piperazine;s.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(pyrimidin-2-yl)-piperazine;t. 1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-benzyl-piperidine;u.1-[(S)-N-tert-butyloxycarbonyl-tyrosyl]-4-(4-fluorophenyl)-piperazine;v. 1-[(S)-N-tert-butyloxycarbonyl-tyrosyl]-4-(o-tolyl)-piperazine; w.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-aminophenyl)-piperazine;x.1-[(S)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-bromo-2-methylphenyl)-piperazine.76. A compound selected from the group of tyrosyl piperazine derivativesconsisting of: a.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-nitrophenyl)-piperazine];b.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(p-tolyl)-piperazine;c.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-chlorophenyl)-piperazine];d.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorophenyl)-piperazine];e.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl-4-(3,4-dichlorophenyl)-piperazine;f.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-cyanophenyl)-piperazine];g.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-chlorophenyl)-piperazine];h.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-methoxyphenyl)-piperazine;i.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-benzylpiperazine;j.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-phenethylpiperazine;k.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-iodophenyl)-piperazine;l.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-acetylphenyl)-piperazine;m.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzyl)-piperazine;n.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzoyl)-piperazine;o.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-nitrobenzyl)-piperazine;p.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-fluorophenyl)-piperazine;q.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(o-tolyl)-piperazine;r.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-methoxyphenyl)-piperazine;s.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(3-chlorophenyl)-piperazine;t.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3-trifluoromethylphenyl)-piperazine;u.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2,3-dimethylphenyl)-piperazine;v.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(pyridin-2-yl)-piperazine;w.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(pyrimidin-2-yl)-piperazine;x.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-benzylpiperazine;y.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-tyrosyl]-4-(4-fluorophenyl)-piperidine;z.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-tyrosyl]-4-(o-tolyl)-piperazine;aa.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-aminophenyl)-piperazine;bb.1-[(S)-O-(3-pyridinesulfonyl)-N-tert-butyloxycarbonyl-tyrosyl]-4-(o-tolyl)-piperazine;y.1-[(S)-O-(3-pyridinesulfonyl)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(phenyl)-piperazine;z.1-[(S)-O-(3-pyridinesulfonyl)-N-tert-butyloxycarbonyl-tyrosyl]-4-(2-methylphenyl)-piperazine;aa.1-[(S)-O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-tyrosyl]-4-(4-bromo-2-methylphenyl)-piperazine.77. A compound selected from the group of tyrosyl piperazine derivativesconsisting of: a.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-nitrophenyl)-piperazine;b.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(p-tolyl)-piperazine;c.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(2-chlorophenyl)-piperazine;d.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-fluorophenyl)-piperazine;e.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(3,4-dichlorophenyl)-piperazine;f.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-cyanophenyl)-piperazine];g.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-chlorophenyl)-piperazine];h.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-methoxy-phenyl)-piperazine;i.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-benzylpiperazine;l.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-phenethyl-piperazine;k.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-iodophenyl)-piperazine];l.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-acetylphenyl)-piperazine];m.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-fluorobenzyl)-piperazine];n.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-fluorobenzoyl)-piperazine];o.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-nitrobenzyl)-piperazine];p.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(2-fluorophenyl)-piperazine];q.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-o-tolyl-piperazine;r.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(2-methoxy-phenyl)-piperazine;s.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(3-chlorophenyl)-piperazine;t.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(3-trifluoromethylphenyl)-piperazine;u.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(2,3-dimethylphenyl)-piperazine;v.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(pyridin-2-yl)-piperazine;w.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(pyrimidin-2-yl)-piperazine;x.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-benzylpiperidine;y.1-[(S)-N,O-bis-(isoquinolinesulfonyl)tyrosyl]-4-(4-fluorophenyl)-piperazine;z. 1-[(S)-N,O-bis-(isoquinolinesulfonyl)tyrosyl]-4-(o-tolyl)-piperazine;aa.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-aminophenyl)-piperazinebb.1-[(S)-N,O-bis-(3-pyridinesulfonyl)-N-methyl-tyrosyl]-4-(4-fluorophenyl)-piperazine;cc.1-[(S)-N,O-bis-(3-pyridinesulfonyl)-N-methyl-tyrosyl]-4-phenyl-piperazine;dd.1-[(S)-N,O-bis-(3-pyridinesulfonyl)-N-methyl-tyrosyl]-4-(2-methylphenyl)-piperazine;ee.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(4-bromo-2-methyl-phenyl)-piperazine;ff.1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(2-methyl-4-[3H]-phenyl)-piperazine.